Neuromodulation Devices and Methods

Abstract

In some aspects, a neuromodulation system configured for placement inside the ear is provided, e.g., having a pressure applicator to bias an electrode toward the ear to promote conduction for auricular nerve stimulation. Also provided in some aspects is a neuromodulation system that can include one or more sensors that measure data from one or more biomarkers of a user's physiological state and an optional controller that uses the measured data to adjust one or more stimulation parameters.

Description

[Technical Field]

[0001] The present disclosure relates to devices, methods, and / or systems for neuromodulation (e.g., non-invasive neurostimulation, etc.) to treat various conditions. Summary of the Invention

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 380,225, filed October 19, 2022, which is incorporated herein by reference in its entirety.

[0003] Wearable systems with compact, ergonomic form factors are needed to increase efficacy, compliance, and comfort while using those systems. In some embodiments, a neuromodulation system is provided comprising an earpiece and an electrical stimulation pulse generator, the electrical stimulation pulse generator configured to deliver a plurality of electrical stimulation pulses to the earpiece, the earpiece configured to be positioned at least partially or completely in, on, or near the ear. In some embodiments, the earpiece comprises a body having a boot. In some embodiments, the boot comprises a housing having a material for placement over a portion of skin. In some embodiments, the boot is configured to rest on a portion of the ear (including, but not limited to, the concha (e.g., the navicular and / or cavity of the concha), the helix, the scaphoid fossa, the antihelix, the triangular fossa, the superior crus, the inferior crus, the helical crus, the tragus, the intertragal notch, the lobe, or the antitragus, or a combination thereof), a first electrode and a second electrode protruding from the boot, a first pressure applicator including a first spring-loaded surface connected to the first electrode, and a second pressure applicator including a second spring-loaded surface connected to the second electrode. The boot may be at least partially made from silicone and designed to rest at the entrance of the ear canal. In some embodiments, the first electrode and the second electrode are configured to deliver multiple 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 external auditory canal, the tragus, and / or the 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 level of a first pressure at the first electrode relative to the ear to decrease 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 level of a second pressure at the second electrode relative to the ear to decrease 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 may be separate from the earpiece or may be integrated into the earpiece. A sensor may or may not be included in certain embodiments with a pressure applicator.

[0004] In some embodiments, the neuromodulation system includes one or more sensors, e.g., measuring biomarkers. Such sensors can be located on, coupled to, or unattached to earpieces or other devices worn, such as on the wrist or leg, and can communicate with them. The sensors may be integrated into a stimulation device, a skin patch, or a belt. One sensor may measure one biomarker, or one sensor may measure two or more biomarkers. The biomarkers may indicate a user condition, such as migraine, colitis, irritable bowel disease, rheumatoid arthritis, high blood pressure, or atrial fibrillation. If the biomarker is higher or lower than a desired level, at least one electrode is configured to deliver electrical stimulation to treat the condition (e.g., symptoms of the condition or the condition itself). In one embodiment, the sensor can detect that the heart rate is too low, too high, or fluctuating, resulting in neural stimulation being provided based on that feedback, either under user control, physician control, or automatically. The neural stimulation can then treat the biomarker (e.g., undesirable heart rate) and / or the underlying condition (cardiac arrhythmia). In another embodiment, a sensor can detect altered electrodermal activity or EEG activity as a biomarker, and based on the detected information, neural stimulation is provided to treat migraines. In yet another embodiment, body temperature is used as a biomarker, and based on the sensor's determination that the temperature is either below or above a desired range, neural stimulation is provided to treat a condition (including, but not limited to, colitis, inflammation, arrhythmia, migraines, or rheumatoid arthritis). The neural stimulation can be provided based on the sensor information under user control, physician control, or automatically. In some embodiments, a closed feedback loop may be used.

[0005] In some aspects, the method provides multiple treatment pathways that depend at least in part on the detection of user biomarkers (e.g., heart rate, heart rate variability, cardiac rhythm, skin sympathetic activity, electrodermal activity, wrist-based temperature, respiratory cycle, brain electrical activity, cytokine levels, physical activity, oxygen levels, etc.). In some embodiments, the biomarkers can include patient demographics, previous medication use, previous device therapy use, and / or sleep cycle. In some embodiments, additional data such as weather or other information at the patient's location (e.g., temperature, humidity, barometric pressure, altitude, etc.) can be monitored to influence stimulation and / or treatment. In one embodiment, a motion sensor can be used to measure physical activity. In one embodiment, a pulse oximeter can be used to measure oxygen levels (e.g., via pulse oximetry). For example, in certain aspects, the method can provide not only acute relief pathways but also symptom reduction and / or preventative therapy pathways depending on the values ​​of the detected biomarkers. Preventative therapy can reduce the onset, number, duration, or severity of symptoms by at least 25-75% or more. As an example, neurostimulation as described herein may significantly reduce the severity or duration of symptoms compared to not using such neurostimulation. For example, depending on the detected level of one or more biomarkers, the wearable device can determine whether the user is likely currently experiencing a condition or is instead about to experience a condition, and then apply peripheral nerve stimulation via a wearable system disclosed herein (e.g., a wrist-worn device, an auricular device, or any combination of a wrist-worn device and an auricular device) that is effective for the treatment pathway the user is actually experiencing at that time.

[0006] 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 detecting one or more biomarkers of the user to enhance the effectiveness of the electrical stimulation. For example, in some embodiments, the wearable system is configured as an earpiece including electrodes, a controller, and at least one sensor. The sensor on the earpiece can be configured to detect levels of one or more biomarkers and provide those levels to the controller for adjusting parameters of the electrical stimulation. Stimulating the vagus nerve in this manner can provide various therapeutic benefits, including treatment of atrial fibrillation or other cardiac arrhythmias, colitis, rheumatoid arthritis, migraines, irritable bowel disease, high blood pressure, etc. The earpiece may be used in conjunction with other neuromodulation devices (e.g., worn on the wrist) to further enhance therapeutic benefits.

[0007] In some embodiments, the wearable systems disclosed herein can determine a user's current respiratory phase and / or when a respiratory phase begins or ends. Being able to accurately determine the respiratory phase can be advantageous for the timing and effectiveness 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 increases treatment efficacy. In some embodiments, the wearable systems include sensors that detect quantitative values ​​related to the user's respiratory state that may not be sufficient alone 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 algorithms that obtain the detected quantitative values ​​and then determine various user parameters (e.g., respiratory threshold, sample check count, respiratory slope threshold, and / or lockout length) that indicate whether the user is inhaling or exhaling.

[0008] Disclosed herein are various embodiments of devices, systems, and methods for delivering electrical neuromodulation (e.g., stimulation of one or more nerves) to a user. In some embodiments, the electrical stimulation is delivered to a region at or near the user's ear. In some embodiments, instead of or in addition to delivering stimulation to a region at or near the ear, the electrical stimulation is delivered to a region at or near the user's wrist. For example, in certain embodiments, an ear device and / or a wrist-worn device secured at least partially within the ear canal applies the electrical stimulation to the user. When electrical stimulation is applied to both locations, the stimulation modality parameters (e.g., frequency, phase, timing, amplitude, offset, etc.) may be complementary to increase effectiveness for treating a condition and / or symptoms of a condition.

[0009] In one embodiment, electrical neuromodulation is delivered via electrodes (e.g., 1, 2, 3, 4, 5, or 6 electrodes). In some embodiments, the electrodes include a substrate and a filler material. In one embodiment, the electrodes are dry electrodes. In some embodiments, dry electrodes can be advantageous by providing a dry skin interface between the electrodes and the user's skin without the need to adhere a hydrogel at the skin interface. The benefits of using dry electrodes are particularly important for body-worn stimulation devices intended for repeated long-term wear. In one embodiment, the electrode material conforms to the body, is flexible, bonds well with the body, and is biocompatible. In one embodiment, a method framework for treating rheumatoid arthritis, atrial fibrillation, or migraine headaches using peripheral nerve stimulation includes one or two treatment pathways: (a) an acute relief pathway, and / or (b) a symptom reduction and / or preventative therapy pathway. In one embodiment, the treatment framework and each treatment pathway can be performed by applying peripheral nerve stimulation via a wrist-worn neuromodulation device, an auricular neuromodulation device, or any combination of a wrist-worn device and an auricular device. In one embodiment, an algorithm for detecting the inspiratory and expiratory phases of breathing is used in conjunction with the electrical neuromodulation described herein. In some embodiments, dry electrodes, unlike wet electrodes, provide a dry skin interface between the electrode and the user's skin without the need for a hydrogel to be adhered at the skin interface. According to some embodiments, the advantages of using dry electrodes are particularly important for body-worn stimulation devices intended for repeated long-term wear. In some embodiments, the electrode material is flexible, which allows the skin interface of the dry electrode to maintain contact with a body surface (e.g., arm, wrist, leg, ear, etc.) during repeated wear. The electrode material is also non-toxic to living tissue (e.g., biocompatible).

[0010] In various embodiments, 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) are treated. In various embodiments, cardiac conditions (such as atrial fibrillation, high blood pressure, and stroke) are treated. Epilepsy and other seizure disorders are treated in one embodiment. Headaches, such as migraines, are treated in another embodiment. In certain embodiments, inflammatory skin conditions and immune dysfunction may also be treated. In some embodiments, cytokine signaling proteins that help control inflammation are affected (e.g., reduced or balanced) by the stimulation.

[0011] In various embodiments, such neuromodulation can be beneficial in treating inflammation (such as neuroinflammation), movement disorders, cardiac disorders, pain, psychiatric disorders, and other conditions. Some of the disclosed devices, systems, and methods can advantageously stimulate a user's vagus (also known as the vagal) nerve while accommodating wide variations in ear anatomy and / or other characteristics across different users. In some embodiments, earpiece and / or stimulation placement is provided at, near, or within one or more of the following locations in or around the concha navicular and / or ear: helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, helical crus, tragus, intertragus, intertragal notch, earlobe, antitragus, and concha cavity, or a combination thereof. In some embodiments, devices are provided that deliver stimulation (e.g., vagus nerve stimulation) via the concha (e.g., the navicular and / or cavity of the concha) and can accommodate large variations in ear anatomy among individuals. Gradual increases or other variations in burst pattern stimulation are provided in some embodiments, which can aid, for example, in patient comfort, compliance, habituation, and / or efficacy. The terms "vagal" and "vagus" can be used interchangeably herein.

[0012] In some embodiments, neuromodulation, such as neurostimulation, as used herein, is used to replace pharmaceuticals, thus reducing undesirable drug side effects. In other embodiments, neuromodulation, such as neurostimulation, is used in conjunction with (e.g., synergistically with) pharmaceuticals, for example, to reduce the dose or duration of drug therapy, thereby reducing undesirable side effects. Undesirable drug side effects include, for example, addiction, tolerance, dependence, gastrointestinal ("GI") problems, nausea, confusion, dyskinesia, appetite changes, and the like. In various embodiments, neuromodulation, such as neurostimulation, is used in conjunction with (e.g., synergistically with) pharmaceuticals to treat inflammatory conditions, such as epilepsy, depression, anxiety, inflammatory bowel disease (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, chronic fatigue syndrome, and in some embodiments, other inflammatory conditions (such as neuroinflammation and inflammatory skin conditions) are treated. Neuromodulation, such as neurostimulation, is used in conjunction with (e.g., synergistically with) medications for treating cardiac conditions (such as atrial fibrillation, high blood pressure, and stroke) in various embodiments. Neuromodulation, such as neurostimulation, is used in conjunction with (e.g., synergistically with) medications for treating headaches, such as migraines, in other embodiments. Neuromodulation may be delivered at the same time of day as a medication is used. Alternatively, neuromodulation may be delivered at a different time of day than a medication is used, or on a different day than a medication is used. When used with the neurostimulation embodiments described herein, a medication may be used at a lower dose, for a shorter period of time, and / or with fewer side effects. For example, the time course or dose of a medication may be reduced by 10-90% (e.g., 10-30%, 30-60%, 60-90%, and overlapping ranges therein) when used with neurostimulation as described herein. Patients may also be able to tolerate drugs or other treatments for longer periods of time when used in conjunction with neurostimulation as described herein because of reduced side effects.

[0013] In some embodiments, the devices described herein (e.g., auricular, leg, or wrist devices) utilize a progressive stimulation burst pattern. In some embodiments, the auricular device utilizes a progressive stimulation burst pattern with respiratory synchronization. In some embodiments, the system may deliver bursts of stimulation pulses at a specific frequency that is dependent on the respiratory cycle (e.g., theta bursts, e.g., in the range of 4-8 Hz). In some embodiments, the auricular device utilizes a progressive stimulation burst pattern without respiratory synchronization. In some embodiments, the system may deliver bursts of stimulation pulses at a specific frequency that is independent of the respiratory cycle (e.g., theta bursts, e.g., in the range of 4-8 Hz). For example, in certain embodiments, the system may progressively increase stimulation intensity at the beginning of each burst of stimulation pulses. A progressive stimulation burst pattern can enhance patient comfort for certain patients (e.g., where synchronized or other stimulation may be uncomfortable or unexpected to the user). For example, when pulses applied to the ear are turned on at full power, there may not be a build-up period to mask the intensity of the stimulation sensation to the ear. A progressive stimulation burst pattern can include a lower stimulation intensity that increases to a higher intensity progressively over the burst to provide a ramp-up to stimulation intensity.

[0014] In one embodiment, a method for determining a user's respiratory phase involves using a sensor to detect and measure respiration. The sensor generates some quantitative measure of the user's respiratory state. In some embodiments, the respiratory state is measured mechanically, electrically, impedance, acoustically (e.g., microphone), ultrasonically, infrared, or video-based. A 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 a respiratory threshold. This threshold is the minimum difference in amplitude between two sample values ​​obtained from the sensor. In one embodiment, a second potential type parameter may be a sample check count. This sample check count is the minimum number of samples in a sequence that need to be checked to consider whether the user has switched from one respiratory phase to another (e.g., from inhalation to exhalation). In one embodiment, a third potential type parameter may be a respiratory slope threshold. The respiratory slope threshold is the minimum slope value for assigning a change from one respiratory phase to another (e.g., from inhalation to exhalation). In one embodiment, a fourth potential parameter may be a lockout length. The lockout length is the minimum amount of time the algorithm is paused. The algorithm may also include a genetic evolutionary 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.

[0015] In some embodiments, the progressive burst pattern is generated by one or more hardware processors of the system (e.g., an ear, leg, or wrist device). In some embodiments, the system can detect an increase or decrease in one or more parameters sensed by one or more sensors selected from the group consisting of a photoplethysmogram sensor (PPG), a galvanic skin 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), and combinations thereof. Based on the detected increase or decrease, the system can tune the bursts of stimulation pulses with respect to the one or more parameters. In some embodiments, the system can tune or change one, two, or more stimulation modality parameters (e.g., frequency, phase, timing, amplitude, offset, etc.) of the bursts of stimulation pulses accordingly. Such tuning can be performed for any of the modalities described herein (e.g., epilepsy, depression, migraine, vagus nerve stimulation (VNS), etc.).

[0016] In some embodiments, a first portion of the auricle device is at least partially secured within the user's ear canal, while a second portion coupled to the first portion is positioned adjacent (e.g., adjacent to, within, or in contact with) the concha navicularis of the user's ear. In some embodiments, contact is made with the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, helical crus, tragus, intertragal notch, lobe, antitragus, cavity of the concha, and / or concha navicularis, or a combination thereof. In some embodiments, the auricle device includes a third portion having a stem and a boss. In some embodiments, the first portion comprises an ear canal element, and the stem is slidably connected to the boss and rotatably connected to the ear canal element via the boss. In some embodiments, a progressive stimulation burst pattern is applied by the neuroeffector (e.g., one, two, four, or six electrodes) of the second portion, gradually increasing in intensity. The progressive stimulation burst pattern can increase in various manners. For example, in some embodiments, a lower stimulation intensity is progressively increased to a higher intensity over multiple pulses of a progressive stimulation burst pattern, hi some embodiments, a lower stimulation intensity is progressively increased to a higher intensity over an initial pulse of a progressive stimulation burst pattern. In some embodiments, the stimulation may increase by 0.05 to 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) over a period of 0.1 to 30 seconds or more (e.g., 0.1 to 0.5, 0.5 to 2, 2 to 5, 5 to 10, 10 to 15, 15 to 30 seconds, and overlapping ranges therein), or the increase may be about a 10 to 50%, 50 to 100%, or 2-fold or 3-fold increase per increment. The difference between the increments may be constant or may vary. For example, the gradual increase or ramp may be from 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 (and higher if desired). Alternatively, the gradual increase or ramp may start at 0.5 mA and increase steadily by 0.2 mA to reach a set point such as 2.5 A.The ramp-up may occur each time stimulation is initially turned on, or may occur as the user increases stimulation during a treatment session. The ramp-up may be adjusted by the user, or may be automated by the system. In some embodiments, a ramp-up is included. In some embodiments, a gradual ramp-up or ramp-up may also be used for non-burst stimulation (such as tonic stimulation).

[0017] In some embodiments, use of the neuromodulation methods or systems described herein for treating a condition and / or its symptoms is provided. Conditions include, but are not limited to, rheumatoid arthritis, atrial fibrillation, and migraine. The method can include positioning a first electrode against a patient's skin adjacent to a first peripheral nerve, positioning a second electrode against the patient's skin adjacent to the first peripheral nerve or a second peripheral nerve, and detecting a level of a biomarker associated with the condition. If the detected level indicates that the user is experiencing the condition, a first electrical stimulus is delivered via the first and second electrodes to provide acute relief therapy. If the detected level indicates that the user is at the onset of the condition, a second electrical stimulus is delivered via the first and second electrodes to provide preventative therapy. The preventative therapy can reduce the onset, number, 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 value of the stimulation modality parameter of the first electrical stimulus is different from the value of the stimulation modality parameter of the second electrical stimulus. Stimulation may be provided to nerves in 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 detected level indicates the user is experiencing a condition, electrical stimulation is delivered via the first electrode and / or the second electrode to provide palliative therapy. In one embodiment, the biomarker is heart rate variability, and if the detected level indicates the user is experiencing or at the beginning of having rheumatoid arthritis, atrial fibrillation, or migraine, electrical stimulation is delivered via the first and / or second electrode to provide treatment (e.g., preventative therapy to reduce the onset, number, duration, or severity of symptoms by at least 25-75% or more (e.g., 25, 40, 50, 70, 90%, etc.)). At least one nerve of the one or more targeted first nerves or 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. Additional sensors and / or electrodes may also be used.

[0018] In some embodiments, the stimulation modality parameter may be amplitude, and the value of the stimulation modality parameter of the first electrical stimulus may be lower than the value of the stimulation modality parameter of the second electrical stimulus. The stimulation modality parameter may be frequency. The stimulation modality parameter may be pulse width. The first electrode and the second electrode may be disposed on a neuromodulation device. The neuromodulation device may be configured as a wrist-worn device. The first electrode and the second electrode may be disposed on the neuromodulation device. The neuromodulation device may be configured to be worn in or near the ear. One of the first electrode (or first electrode set) and the second electrode (or second electrode set) may be configured to be disposed on a user's wrist, and the other of the first electrode and the second electrode may be configured to be worn in or near another location (such as the ear, the other wrist, or the leg).

[0019] In some embodiments, the detection of biomarker levels can be performed during the detection phase, and acute palliative therapy and preventive therapy can be performed during the treatment delivery phase and after the detection phase. The detection of biomarker levels 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 the neuromodulation device. The detection phase can be performed by patient self-reporting of symptoms.

[0020] In some embodiments, the therapy delivery phase can be initiated by prompting the user to begin delivery of a first electrical stimulus to provide acute relief therapy or a second electrical stimulus to provide preventative therapy. In one embodiment, the therapy delivery phase can be initiated automatically after the detected levels indicate that the user has, for example, rheumatoid arthritis, atrial fibrillation, or migraine, or that the user is at the beginning of having rheumatoid arthritis, atrial fibrillation, or migraine. In one embodiment, the preventative therapy reduces the onset, number, duration, or severity of future symptoms by at least 25-75% or more (e.g., 25, 40, 50, 70, 90%, etc.).

[0021] In some embodiments, the measured biomarkers may be at least one of heart rate, heart rate variability, cardiac rhythm, skin sympathetic activity, electrodermal activity, wrist or ear temperature, respiratory cycle, brain electrical activity, and / or cytokine levels. Biomarkers may be measured by sensors placed on the body (e.g., ear, forehead, scalp or other part of head, wrist or other part of arm, ankle or other part of leg, chest, etc.). Machine learning algorithms may be used to assess when to initiate a treatment delivery phase depending at least on the detected level of the biomarker. A predetermined threshold for heart rate may be greater than 90, 100, 110, or 120 beats per minute, and acute relief therapy may be applied when the detected level exceeds the predetermined threshold. In some embodiments, the method provides multiple treatment pathways that depend at least in part on the detection of user biomarkers (e.g., heart rate, heart rate variability, cardiac rhythm, skin sympathetic activity, electrodermal activity, wrist temperature, respiratory cycle, brain electrical activity, cytokine levels, physical activity, oxygen levels, etc.). In some embodiments, biomarkers may include patient demographics, previous medication use, previous device therapy use, and / or sleep cycles. In some embodiments, additional data, such as weather information at the patient's location (e.g., temperature, humidity, barometric pressure, altitude), may be monitored to influence stimulation and / or treatment. In one embodiment, a motion sensor may be used to measure physical activity. In one embodiment, a pulse oximeter may be used to measure oxygen levels (e.g., via pulse oximetry). Biomarkers may be detected immediately before, during, and / or after therapeutic stimulation. In another embodiment, biomarkers are detected hours or days before or after stimulation. For example, blood tests may be used to determine elevated biomarkers, such as cytokines or other inflammatory compounds, and stimulation is administered as a treatment to reduce such biomarkers. In some embodiments, other bodily fluids, such as urine, saliva, sweat, tears, nasal discharge, etc., are used to determine biomarkers.These may be measured using sensors that are separate (eg, independent) from or in communication with the neuromodulatory components described herein.

[0022] In some examples, a predetermined threshold of heart rate variability can exceed 1, 2, 3, 4, or 5, and neural stimulation (e.g., prophylactic therapy) can be applied when the detected level exceeds the predetermined threshold. The predetermined threshold can be determined on a case-by-case basis and is patient-specific.

[0023] In some embodiments, at least one of the first electrical stimulus or the second electrical stimulus can be delivered in bursts of pulses. In some embodiments, the burst frequency of the stimulation can be any value between 0 Hz and 15 Hz or 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 50 Hz and 150 Hz.

[0024] In some embodiments, the electrical stimulation is delivered in bursts of pulses. In some embodiments, the stimulation burst frequency can be any value between 0 Hz and 15 Hz or between 4 Hz and 12 Hz. In some embodiments, the stimulation pulse frequency can be any value between 0 Hz and 200 Hz or between 50 Hz and 150 Hz. In some embodiments, the stimulation burst frequency can be any value between 0 Hz and 15 Hz or between 1 Hz and 14 Hz. In some embodiments, the stimulation pulse frequency can be any value between 0 Hz and 150 Hz or between 1 Hz and 149 Hz.

[0025] 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 earpiece positioned inside the ear. The earpiece can include two electrodes protruding from the top of the boot that rest on the concha of the ear to stimulate the auricular branch of the vagus nerve and / or other nerves that innervate the ear, one or more sensors that measure data from one or more biomarkers of the user's physiological state, and a controller that receives and uses the measured data to adjust one or more stimulation parameters of the electrical stimulation pulses. In some embodiments, the boot includes a housing having a material for placement over a portion of the skin. The boot may be at least partially made of silicone and designed to rest at the entrance of the ear canal.

[0026] In some embodiments, the 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 attach to an article of clothing via a clip. In some embodiments, the electrical stimulation pulse generator can be integrated into an earpiece, providing a device that resembles a hearing aid in appearance.

[0027] In some embodiments, the neuromodulation device can further include a wristwatch-like, wrist-worn stimulation device that delivers electrical stimulation to peripheral nerves located at the wrist. The stimulation device can include a band including two rows of three electrodes, with a central electrode of each row being a stimulation electrode and electrodes on either side of the central electrode being charge-balancing electrodes. The stimulation device can further include a second wrist-worn electrical stimulation pulse generator that delivers bursts of electrical stimulation pulses to the electrodes on the band, a user interface including a display on the face of the watch-like device, and a base station configured to charge and store the watch-like device.

[0028] 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 cardiac rhythm. In some embodiments, the electrocardiogram is integrated into a stimulator of a watch-like device. In some embodiments, the electrocardiogram is integrated into the base station. In some embodiments, the electrocardiogram is integrated into a patch worn on the user's body.

[0029] In some embodiments, one of the sensors is a sensor for detecting a biomarker of skin sympathetic nerve activity. In some embodiments, one of the sensors is a sensor for detecting electrodermal activity. In some embodiments, one of the sensors is a sensor for detecting skin temperature. In some embodiments, one of the sensors is a mechanical sensor integrated into a belt worn around the chest that detects changes in respiratory cycle.

[0030] In some embodiments, the electrical stimulation pulse generator communicates wirelessly with the belt respiratory sensor and delivers electrical stimulation via a conduit to an earpiece. The earpiece can be a silicone boot that rests at the entrance to the ear canal. The earpiece can be a clip that attaches to the helix of the ear and includes a reflective or transmissive photoplethysmography sensor.

[0031] In some embodiments, one of the sensors is a microphone worn in the ear to detect changes in the user's breathing cycle. In some embodiments, one of the sensors measures temperature within the ear. In some embodiments, one of the sensors is an infrared reflected light monitor integrated into the earpiece to detect changes in the user's breathing 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 cytokine levels in the body and is integrated into a stimulation device, a skin patch, or a belt.

[0032] In some embodiments, the systems and methods are used to provide acute treatment to a user suffering from migraines, colitis, irritable bowel disease, rheumatoid arthritis, high blood pressure, episodes of atrial fibrillation, or other cardiac arrhythmias or conditions. In some embodiments, the systems and methods are used to prevent or reduce the severity or frequency of future episodes of atrial fibrillation or other cardiac arrhythmias.

[0033] In some embodiments, the earpiece can include a pressure applicator configured to bias the two electrodes toward the ear. In one embodiment, the earpiece can include two electrodes that protrude or otherwise extend from the top of the boot. In some embodiments, the boot includes a housing having a material for placement on a portion of the skin. The boot may be made at least partially from silicone and designed to rest at the entrance of the ear canal. The pressure applicator(s) can be configured to increase the level of pressure applied by the two electrodes against the ear to lower the impedance between the two electrodes and the ear. The pressure applicator can include, for example, the following structural and / or functional features: actuation surface(s), such as a spring-loaded actuation surface, or other pressure application modality (e.g., gas pressure, fluid pressure, foam pressure, magnetic, and / or temperature-changing material pressure configuration). The pressure applicator is used to increase contact of the electrodes with the skin on or near the ear, but can also be used for the same purposes as electrodes used on other parts of the body, such as the arm (e.g., wrist) or leg. In some embodiments, the neuromodulation (e.g., neurostimulation) device uses means to apply pressure, bring the electrodes into closer contact with the skin, increase conductivity, reduce impedance, or a combination of these functions.

[0034] In some embodiments, a system for determining a user's respiratory phase is provided. The system may include a sensor for detecting and measuring a quantified value generally associated with the user's respiratory phase. The quantified value may be one or more of a respiratory threshold, a sample check count, a respiratory slope threshold, and a lockout length. The system further includes a controller configured to apply an algorithm to the quantified value and determine the user's respiratory phase based on the application of the algorithm to the quantified value. The quantified value may be a respiratory threshold, and the respiratory threshold may be a minimum difference in amplitude between two sample values. The quantified value may be a sample check count, and the sample check count may be a minimum number of samples in a sequence that need to be checked to consider whether the user has switched from one respiratory phase to another. The quantified value may be a respiratory slope, and the respiratory slope threshold may be a minimum slope value required to assign a change from one respiratory phase to another. The quantified value may be a lockout length, and the lockout length may be a minimum amount of time the algorithm is paused. The determined respiratory phase may be an inspiratory phase or an expiratory phase. In some embodiments, the respiratory phase or other respiratory data may then be used as a biomarker for initiating or increasing stimulation of one or more nerves.

[0035] In some embodiments, the value of the stimulation modality parameter of the first electrical stimulus is different from the value of the stimulation modality parameter of the second electrical stimulus. In some embodiments, the value of the stimulation modality parameter of the first electrical stimulus is the same as the value of the stimulation modality parameter of the second electrical stimulus.

[0036] Any one of the devices described herein can be used to prevent (e.g., reduce symptoms of, and / or treat) 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 of Parkinson's disease), 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), cardiac conditions (such as atrial fibrillation, high blood pressure, stroke), epilepsy and / or seizures, headaches (such as migraines), and inflammatory skin conditions and immune dysfunction.

[0037] In some embodiments, an auricular device for non-invasive neuromodulation comprises 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, in, or in contact with) the user's ear when the first portion is at least partially secured within the user's ear canal. The second portion comprises a neuroeffector (e.g., one or more electrodes or means for delivering electrical stimulation) configured to modulate one or more nerves in or around the ear. The neuroeffector can include at least a first and / or second electrode, and the neuroeffector 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 and return electrodes can be spaced apart from each other by a distance of about 10 mm to about 15 mm. In some embodiments, the distance is approximately 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 neuroeffector is configured to apply a normal force to the ear (e.g., at the navicularis concha, cavity of the concha, helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, helical crus, tragus, intertragal notch, earlobe, and / or antitragus, or a combination thereof) when the first portion of the auricle device is at least partially secured within the user's ear canal. In some embodiments, the normal force is from about 0.01 Newtons (N) to about 1 Newton (N) (e.g., 0.01-0.05 N, 0.05-0.05 N, 0.01-0.1 N, 0.1-0.5 N, 0.5-1 N, and overlapping ranges therein). In some embodiments, the vagus nerve, trigeminal nerve, and / or greater auricular nerve are neuromodulated. In some embodiments, only the vagus nerve (e.g., the auricular branch of the vagus nerve or a non-auricular branch) is neuromodulated. In some embodiments, the vagus nerve (e.g., the auricular branch of the vagus nerve or a non-auricular branch) and one, two, or more other nerves are neuromodulated (e.g., the trigeminal nerve, the greater auricular nerve, a nerve of the auricular branch, the auricular branch of the vagus nerve, the facial nerve, the auricular temporal nerve, etc.).In some embodiments, the vagus nerve (e.g., the auricular or non-auricular branch of the vagus nerve) is not stimulated, but instead, for example, another nerve is stimulated (e.g., the trigeminal nerve, the greater auricular nerve, the facial nerve, the auriculotemporal nerve, other nerves in the auricular branch, etc.). Neuromodulation according to some embodiments includes, for example, stimulation using the parameters disclosed herein. In one embodiment, a second treatment (e.g., vibration therapy) is provided in conjunction with the neurostimulation.

[0038] In some embodiments, the first portion can include an ear canal element, the second portion can include at least one prong, and the auricle device can further include a stem connecting the ear canal element to the at least one prong. In some embodiments, the nerve effector comprises an active electrode and a return electrode. In some embodiments, the active electrode and the return electrode are positioned along at least one prong. In some embodiments, the at least one prong includes a first prong and a second prong, each having a first end connected to the stem and a second end opposite the first end, the active electrode being positioned at the second end of the first prong, and the return electrode being 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 of about 10 mm to about 15 mm. In some embodiments, the distance is about 11 to 13 mm (e.g., 11.5 mm). In some embodiments, the diameter of the electrode-skin contact surface area of ​​each of the active and return electrodes is about 2 mm to about 8 mm (e.g., 2 to 4, 3 to 5, 4 to 6, 6 to 8 mm, and overlapping ranges therein). In some embodiments, the diameter of the electrode-skin contact surface area of ​​each of the active and return electrodes is about 3 to 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 of about 20° to about 90° (e.g., 20° to 30°, 30° to 40°, 40° to 50°, 50° to 60°, 60° to 70°, 70° to 80°, 80° to 90°, and overlapping ranges therein). In some embodiments, the first prong has a longer length than the second prong. In some embodiments, the second prong has a longer length than the first prong, hi some embodiments, one or more of the prongs are not rotatable and / or bendable (e.g., relative to the stem).In one embodiment, the boss provides sufficient adjustability (eg, allows for a specific rotation) without requiring prong rotation and / or bendability.

[0039] The ear device may further comprise 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 while coupled with the stem and ear canal element. In some embodiments, the boss is configured to allow the ear canal element to rotate relative to the stem while coupled with the stem and ear canal element. In some embodiments, the boss comprises a pocket configured to receive the stem. In some embodiments, the pocket surrounds a portion of the periphery of the cross section of the stem when the boss is coupled with the stem. In some embodiments, the pocket includes a protrusion, and the stem includes one or more notches recessed from a surface of the stem, the one or more notches 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).

[0040] The auricular device may further comprise a power source configured to provide power to the neuro-effector. The power source may be, for example, one or more batteries (e.g., rechargeable batteries). In one embodiment, the power source is located on the device coupled to the ear or in a location other than the ear, such as the wrist or elsewhere on or within the body.

[0041] In some embodiments, the first portion includes an ear canal element, the second portion includes at least one prong, and the auricle device can further include a stem connecting the ear canal element to the at least one prong, and the neural effector comprises an active electrode and a return electrode. In some embodiments, the at least one prong is flexible. In some embodiments, the at least one prong is elastic. 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, the active electrode being positioned at the second end of the first prong, and the return electrode being positioned at the second end of the second prong. In some embodiments, the first prong and the second prong are configured to allow each of the active electrode and the return electrode to simultaneously and independently contact a portion of the ear (e.g., the navicularis concha). In some embodiments, the first prong and the second prong are configured to apply a normal force to the ear (e.g., the navicular cavity of the concha, the cavity of the concha, the helix, the scaphoid fossa, the antihelix, the triangular fossa, the superior crus, the inferior crus, the helical crus, the tragus, the intertragal notch, the lobe, and / or the antitragus, or a combination thereof) when the ear canal element is at least partially secured within the user's ear canal. In some embodiments, the normal force is from about 0.01 N to about 1 N. In some embodiments, at least one of the first prong and the second prong is flexible and / or elastic. In some embodiments, only one of the first prong and the second prong is flexible and / or elastic. In some embodiments, both the first prong and the second prong are flexible and / or elastic. In some embodiments, the stem is rigid. In some embodiments, the second ends of the first prong and the second prong are spaced apart from one another. Additional prongs may also be used.

[0042] In some embodiments, an auricular device for non-invasive vagus nerve modulation includes an ear canal element configured to be at least partially secured within a user's ear canal, a boss rotatably coupled to the ear canal element, a stem slidably coupled to the boss and rotatable relative to the ear canal element via the boss, at least one prong coupled to the stem, and a neuroeffector coupled to an end of the at least one prong. The stem and the at least one prong can be configured to position the neuroeffector in, on, or near the user's ear when the ear canal element is at least partially secured in or within the user's ear canal.

[0043] In some embodiments, an auricular device for non-invasive vagus nerve modulation utilizing a stimulation burst pattern includes a first portion configured to be at least partially secured within a user's ear canal, a second portion coupled to the first portion and configured to be positioned within the concha of the user's ear when the first portion is at least partially secured within the user's ear canal, and one or more hardware processors configured to generate the stimulation burst pattern. The second portion can include a neuroeffector configured to apply the stimulation burst pattern to modulate the user's vagus nerve.

[0044] In some embodiments, the auricular device further comprises 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 photoplethysmogram sensor (PPG), a galvanic skin 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 with mechanical, electrical, impedance, acoustic (e.g., microphone), ultrasonic, infrared, or video-based measures. In some embodiments, the one or more sensors can be utilized to measure response to therapy and to calibrate therapy. In some embodiments, the auricular device is configured to electrically connect to a power source separate from the auricular device.

[0045] 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 and / or return electrodes, (ii) an adhesive material adjacent to the active and / or return electrodes, (iii) any transcutaneous components, and / or (iv) any implantable components. Some embodiments include a battery and / or a cable, while other embodiments do not.

[0046] 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, the stimulation waveform including a progressive burst pattern, 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 photoplethysmogram sensor (PPG), a galvanic skin 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).

[0047] In some embodiments, depression (including but not limited to, postpartum depression, depression associated with neurological disorders, major depression, seasonal affective disorder, depressive disorders, etc.), inflammation (such as neuroinflammation), Lyme disease, neurological disorders (such as Parkinson's disease and Alzheimer's disease), and gastrointestinal problems (including those of Parkinson's disease). Inflammatory bowel disease (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, and other inflammatory diseases are treated in some embodiments. Inflammatory skin conditions can also be treated.

[0048] In some embodiments, cardiac conditions (such as atrial fibrillation, high blood pressure, and stroke) are treated in one embodiment. Epilepsy and other seizure disorders are treated in one embodiment. Headaches, such as migraines, are treated in another embodiment. The neuromodulation devices, e.g., neurostimulation 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 using peripheral nerve stimulation includes multiple treatment pathways: (a) an acute relief pathway, and / or (b) a preventative therapy pathway. In one embodiment, the treatment framework and each treatment pathway can be implemented by applying peripheral nerve stimulation via a wrist-worn neuromodulation device, an auricular neuromodulation device, or any combination of a wrist-worn device and an auricular device. In some embodiments, a device for stimulating nerves in the legs is also provided.

[0049] In some embodiments, the devices described herein can be used to treat chronic inflammatory conditions and flare-ups. Bradykinesia, dyskinesia, gait dysfunction, dystonia, and / or rigidity can also be treated according to some embodiments. In some embodiments, rehabilitation as a result of a specific event, such as rehabilitation from a stroke or other cardiovascular event, is treated. In some embodiments, systems and methods are provided for reducing habituation and / or tolerance to stimulation in the disorders and conditions identified herein, for example, by introducing variability in the stimulation parameter(s) described herein.

[0050] In some embodiments, a system for applying neuromodulation to a subject includes multiple neuromodulation devices positioned on or near different parts of the subject's body. For example, such a system can include a first neuromodulation device (such as any of the auricle devices described herein) positioned on or near the subject's ear, and a second neuromodulation device positioned on or near a different part of the subject's body (e.g., wrist, palm, finger, part of arm, leg, ankle, foot, sole, toe, etc.). One, two, three, or four neuromodulation devices may be worn by the subject. When two or more neuromodulation devices are used, they may be operated separately or together (e.g., synchronized). Vagus nerve modulation is achieved using a device described herein, according to some embodiments. In some embodiments, the device described herein is used to stimulate the autonomic nervous system. In some embodiments, the device described herein is used to balance the sympathetic / parasympathetic nervous system. In some embodiments, improvement in the condition being treated is one indicator that such balancing has occurred. For example, reduction in one or more of tremor, inflammation, cardiac abnormalities, imbalance, movement disorders, headache, pain, etc. after use of a neuromodulation device described herein (compared to before use) is used in some embodiments to indicate balancing of the sympathetic / parasympathetic nervous system. Balancing can also be indicated by measuring neurotransmitters and showing improvements in neurotransmitter function, quantity, activity, uptake, etc.

[0051] In some embodiments, neuromodulation (e.g., vagus nerve neuromodulation) using the devices and methods described herein affects (increases, decreases, or maintains) the release, uptake, and / or metabolism of neurotransmitters. To achieve a desired effect, certain neurotransmitters can be increased, while others can be decreased. The dopaminergic system and / or the serotonergic system are modulated according to some embodiments described herein. In some embodiments, the brain-gut axis is modulated using the devices and methods described herein.

[0052] Although some embodiments herein disclose neurostimulation, it should be understood that downregulation of various pathways may be achieved. For example, cytokine production and / or activity may be inhibited to treat inflammation (including various arthritic conditions, gastrointestinal disorders, etc.). The production and / or activity of certain neurotransmitters may be reduced. The uptake and / or metabolism of neurotransmitters may be increased.

[0053] Methods of using the systems described herein are also provided. For example, in some embodiments, a method for modulating a subject's vagus nerve includes generating, using one or more hardware processors, a stimulation waveform for stimulation using one or more electrodes, the stimulation waveform including a progressive burst pattern, and applying the stimulation waveform to a portion of the subject's body using one or more electrodes. In some embodiments, the method further includes determining one or more physiological parameters of the subject using a physiological sensor and modifying the stimulation waveform based on the one or more physiological parameters. In some embodiments, the method further includes determining motion data of the subject using an inertial measurement unit sensor (IMU) and modifying the stimulation waveform based on the motion data. In some embodiments, the physiological sensor includes a photoplethysmography (PPG) sensor. In some embodiments, the physiological sensor includes a galvanic skin sensor (GSR). In some embodiments, the physiological sensor includes an electroencephalography (EEG) sensor or a sensor measuring temperature.

[0054] In some embodiments, a method for 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, the second portion includes a neuroeffector, and the method further includes at least partially securing the first portion within the subject's ear canal. Additional electrodes may also be used.

[0055] In some embodiments, the first portion includes an ear canal element, and the second portion includes at least one prong configured to operably position a neural effector adjacent (e.g., adjacent to, in, or contacting) a portion of the subject's ear, the neuromodulation device further includes a stem connecting the ear canal element to the at least one prong, and the method further includes adjusting a 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 neuromodulation device further includes a boss configured to couple the ear canal element to the stem and allow the ear canal element to move along a portion of the length of the stem. In some embodiments, the ear canal element is rotatably coupled to the stem, and adjusting the position of the ear canal element relative to the stem includes rotating the ear canal element. In some embodiments, the neuromodulation device further includes a boss configured to rotatably couple the ear canal element to the stem and allow the ear canal element to rotate while coupled to the stem.

[0056] In some embodiments, the method further includes positioning the neuroeffector adjacent to (e.g., adjacent to, in, or in contact with) the concha navicularis or other portion of the subject's ear, such as the cavity of the concha, the helix, the scaphoid fossa, the antihelix, the triangular fossa, the superior crus, the inferior crus, the helical crus, the tragus, the intertragal notch, the earlobe, and / or the antitragus, or a combination thereof. In some embodiments, the first neuroeffector and the second neuroeffector (e.g., an electrode or other means for delivering electrical pulses or energy) are separated from each other by a distance. In some embodiments, the distance is about 10 mm to about 15 mm. In some embodiments, the distance is about 11.5 mm. In some embodiments, the method further includes applying a normal (e.g., vertical) force in or around the ear using the neuroeffector. In some embodiments, the normal force is about 0.01 N to about 1 N.

[0057] In some embodiments, vagal activity is downregulated, upregulated, or both (e.g., balanced) using the devices described herein. In various embodiments, the devices described herein can be used to apply vagal neuromodulation to increase neurotransmitter release, uptake, and / or metabolism. In some aspects, neuromodulation is used to affect (e.g., reduce or increase) neurotransmitter release, uptake, and / or metabolism. Some embodiments apply vagal neuromodulation to balance neurotransmitter release, uptake, and / or metabolism by both increasing and decreasing neurotransmitter activity. Some embodiments apply vagal neuromodulation to activate or downregulate the dopaminergic and / or serotonergic systems. Some embodiments apply vagal neuromodulation to modulate the brain-gut axis. Some embodiments are used to treat depression (including, but not limited to, postpartum depression, depression associated with neurological disorders, major depression, seasonal affective disorder, depressive disorders, etc.), inflammation (such as neuroinflammation), Lyme disease, neurological disorders (such as Parkinson's disease and Alzheimer's disease), and gastrointestinal issues (including those of Parkinson's disease). Some embodiments are used to treat inflammatory bowel disease (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, osteoarthritis, psoriasis, and other inflammatory diseases. In some embodiments, the devices described herein are used to treat inflammatory skin conditions, chronic The devices and methods described herein can be used to treat chronic fatigue syndrome, and / or chronic inflammatory conditions and flare-ups. In some embodiments, vascular modulation (either dilation or constriction) is provided using the devices and methods described herein (e.g., through neurostimulation). Such treatment can reduce inflammation (including, but not limited to, inflammation following microbial infection). In various embodiments, the devices and methods described herein can increase, decrease, or otherwise balance vasodilation and vasoconstriction through neuromodulation (e.g., modulation of the vagus nerve, trigeminal nerve, and / or other nerves in or around the ear).In some embodiments, a reduction in vasodilation is provided, for example, to treat or prevent migraines or other conditions exacerbated by vasodilation. In other embodiments, vasoconstriction is reduced, for example, in conditions where dilation is beneficial (e.g., hypertension and painful conditions). In one embodiment, the reduction in inflammation treats tinnitus. In some embodiments, modulation of blood vessels (either dilation or constriction) is used to treat tinnitus. Tinnitus can be treated, according to some embodiments, through modulation (e.g., stimulation) of the vagus nerve (e.g., the non-auricular portion of the vagus nerve), alone or in combination with one, two, or more other nerves (e.g., including the trigeminal nerve, the greater auricular nerve, the nerves of the auricular branch, the auricular branch of the vagus nerve, the facial nerve, the auriculotemporal nerve, etc.). In one embodiment, a nerve other than the vagus nerve is modulated to treat tinnitus. In some embodiments, the cranial / auditory nerve may be modulated to treat tinnitus and / or auricular inflammation.

[0058] Neuromodulation, such as neurostimulation, as described in several embodiments herein, can provide therapeutic benefits across 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), urinary system disorders, gastrointestinal disorders, cardiac 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 some embodiments. In one embodiment, cardiac conditions (such as atrial fibrillation, hypertension, and stroke) are treated. Epilepsy and other seizure disorders are treated in one embodiment. In some embodiments, inflammatory skin conditions and immune dysfunction are also treated.

[0059] 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 conditions. Disorders include, but are not limited to, tetanus, meningitis, Lyme disease, urinary tract infections, mononucleosis, chronic fatigue syndrome, autoimmune disorders, and the like. In some embodiments, autoimmune disorders and / or pain unrelated to microbial infection are treated, including, for example, inflammation (e.g., neuroinflammation), headache, back pain, joint pain and stiffness, muscle pain and tension, and the like.

[0060] In some 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 some embodiments, the devices described herein can be used to treat immune dysfunction. Some embodiments stimulate or otherwise modulate the autonomic nervous system, more specifically to treat diseases or disease symptoms exacerbated by autonomic dysfunction, including, but not limited to, depression, anxiety, insomnia, hypertension, cardiac arrhythmias, overactive bladder, inflammatory bowel disease (e.g., Crohn's disease, colitis, and functional dyspepsia), fecal incontinence, headaches and migraines, chronic pain, vagal syncope, inflammatory diseases (e.g., rheumatoid arthritis, lupus, and other autoimmune diseases), and tinnitus. Some embodiments use wearable devices to balance the sympathetic / parasympathetic nervous system, more specifically to treat diseases associated with an imbalance in the autonomic nervous system, including, but not limited to, tremors, cardiac disorders, mental health disorders, or another disease or condition as disclosed elsewhere herein.

[0061] Other disorders may also be treated using the embodiments described herein. For example, stimulation of the vagus nerve has been shown to improve symptoms of hypertension, dexterity, and cardiac arrhythmias.

[0062] For purposes of summarizing the present disclosure, certain aspects, advantages, and novel features are described herein. It is to be understood that not necessarily all such aspects, advantages, or features may be embodied in any particular embodiment of the present disclosure. The present disclosure supports countless combinations of such aspects, advantages, or features. [Brief explanation of the drawings]

[0063] Certain features of the present disclosure are described below with reference to the drawings. The illustrated embodiments are intended to illustrate, but not limit, the embodiments. Various features of different disclosed embodiments can be combined to form additional embodiments that are part of this disclosure.

[0064] [Figure 1A] FIG. 1 illustrates a user's ear according to aspects of the present disclosure.

[0065] [Figure 1B] FIG. 1 is a schematic diagram illustrating exemplary contact locations of electrodes for delivering neural stimulation within the ear, according to aspects of the present disclosure.

[0066] [Figure 1C] 10A-10D illustrate embodiments of electrode ring interfaces according to aspects of the present disclosure. [Figure 1D] 10A-10D illustrate embodiments of electrode ring interfaces according to aspects of the present disclosure. [Figure 1E] 10A-10D illustrate embodiments of electrode ring interfaces according to aspects of the present disclosure. [Figure 1F] 10A-10D illustrate embodiments of electrode ring interfaces according to aspects of the present disclosure.

[0067] [Figure 1G] FIG. 1 illustrates an experimental setup for measuring applied force or pressure and its relationship to impedance, according to various embodiments of the present disclosure. [Figure 1H]FIG. 1 illustrates an experimental setup for measuring applied force or pressure and its relationship to impedance, according to various embodiments of the present disclosure. [Figure 1I] FIG. 1 illustrates an experimental setup for measuring applied force or pressure and its relationship to impedance, according to various embodiments of the present disclosure. [Figure 1J] FIG. 1 illustrates an experimental setup for measuring applied force or pressure and its relationship to impedance, according to various embodiments of the present disclosure. [Figure 1K] FIG. 1 illustrates an experimental setup for measuring applied force or pressure and its relationship to impedance, according to various embodiments of the present disclosure.

[0068] [Figure 1L] 1A-1C illustrate electrodes with pressure applicators according to various embodiments of the present disclosure. [Figure 1M] 1A-1C illustrate electrodes with pressure applicators according to various embodiments of the present disclosure.

[0069] [Figure 2A] FIG. 1 is a perspective view of an embodiment of an auricle device for delivering neural stimulation in accordance with aspects of the present disclosure.

[0070] [Figure 2B] FIG. 2B is an enlarged perspective view of the ear device of FIG. 2A according to an embodiment of the present disclosure. [Figure 2C] FIG. 2B is an enlarged perspective view of the ear device of FIG. 2A according to an embodiment of the present disclosure.

[0071] [Figure 2D] FIG. 2B is a side view of the auricle device of FIG. 2A according to an embodiment of the present disclosure. [Figure 2E] FIG. 2B is a side view of the auricle device of FIG. 2A according to an embodiment of the present disclosure.

[0072] [Figure 2F] FIG. 2B is a top view of the auricle device of FIG. 2A according to an embodiment of the present disclosure. [Figure 2G] FIG. 2B is a bottom view of the auricle device of FIG. 2A according to an embodiment of the present disclosure.

[0073] [Figure 2H] FIG. 2B illustrates a portion of the auricle device of FIG. 2A according to an embodiment of the present disclosure. [Figure 2I] FIG. 2B illustrates a portion of the auricle device of FIG. 2A according to an embodiment of the present disclosure. [Figure 2J] FIG. 2B illustrates a portion of the auricle device of FIG. 2A according to an embodiment of the present disclosure.

[0074] [Figure 2K] FIG. 2B illustrates a portion of the auricle device of FIG. 2A according to an embodiment of the present disclosure. [Figure 2L] FIG. 2B illustrates a portion of the auricle device of FIG. 2A according to an embodiment of the present disclosure. [Figure 2M] FIG. 2B illustrates a portion of the auricle device of FIG. 2A according to an embodiment of the present disclosure.

[0075] [Figure 2N] FIG. 2B is a rear view of the auricle device of FIG. 2A according to an embodiment of the present disclosure. [Figure 2O] FIG. 2B is a front view of the auricle device of FIG. 2A according to an embodiment of the present disclosure.

[0076] [Figure 3] FIG. 10 illustrates another embodiment of an auricle device for delivering neural stimulation in accordance with aspects of the present disclosure.

[0077] [Figure 4] 10 illustrates an embodiment of a boss that may be incorporated into any of the auricle devices disclosed herein.

[0078] [Figure 5A] FIG. 10 illustrates another embodiment of an auricle device for delivering neural stimulation in accordance with aspects of the present disclosure. [Figure 5B] FIG. 10 illustrates another embodiment of an auricle device for delivering neural stimulation in accordance with aspects of the present disclosure.

[0079] [Figure 5C] 5A-5B illustrate how the pinna device of FIGS. 5A-5B can be adjusted for compatibility with different ear anatomies. [Figure 5D] 5A-5B illustrate how the pinna device of FIGS. 5A-5B can be adjusted for compatibility with different ear anatomies.

[0080] [Figure 6A] FIG. 10 illustrates another embodiment of an auricle device for delivering neural stimulation in accordance with aspects of the present disclosure. [Figure 6B] FIG. 10 illustrates another embodiment of an auricle device for delivering neural stimulation in accordance with aspects of the present disclosure.

[0081] [Figure 7] FIG. 10 illustrates another embodiment of an auricle device for delivering neural stimulation in accordance with aspects of the present disclosure.

[0082] [Figure 8A] FIG. 1 is a block diagram of an exemplary neuromodulation (e.g., neurostimulation) device.

[0083] [Figure 8B] FIG. 8B is a block diagram of a user interface device that can be connected to the neurostimulator device of FIG. 8A.

[0084] [Figure 8C] FIG. 8C is a block diagram of an embodiment of a controller that can be implemented using some or all of the hardware components described with respect to FIG. 8A or 8B.

[0085] [Figure 9A] FIG. 8B illustrates an exemplary stimulation pattern that can be applied using the neuromodulation device of FIG. 8A. [Figure 9B]FIG. 8B illustrates an exemplary stimulation pattern that can be applied using the neuromodulation device of FIG. 8A. [Figure 9C] FIG. 8B illustrates an exemplary stimulation pattern that can be applied using the neuromodulation device of FIG. 8A.

[0086] [Figure 10] FIG. 1 illustrates a framework including cardiac measurement tasks, acute palliative therapy, and preventative therapy, according to one embodiment of the present disclosure.

[0087] [Figure 11] FIG. 1 illustrates a neuromodulation device delivering electrical stimulation to the auricular branch of the vagus nerve, according to an embodiment of the present disclosure. [Figure 12] FIG. 1 illustrates a neuromodulation device delivering electrical stimulation to the auricular branch of the vagus nerve, according to an embodiment of the present disclosure.

[0088] [Figure 13] FIG. 1 illustrates a device for delivering electrical stimulation to the auricular branch of the vagus nerve using an additional stimulation device, according to an embodiment of the present disclosure.

[0089] [Figure 14A] FIG. 1 illustrates a neuromodulation device delivering electrical stimulation to the auricular branch of the vagus nerve, according to an embodiment of the present disclosure. [Figure 14B] FIG. 1 illustrates a neuromodulation device delivering electrical stimulation to the auricular branch of the vagus nerve, according to an embodiment of the present disclosure.

[0090] [Figure 15A] FIG. 1 illustrates a neuromodulation device delivering electrical stimulation to the auricular branch of the vagus nerve, according to an embodiment of the present disclosure. [Figure 15B] FIG. 1 illustrates a neuromodulation device delivering electrical stimulation to the auricular branch of the vagus nerve, according to an embodiment of the present disclosure. [Figure 15C] FIG. 1 illustrates a neuromodulation device delivering electrical stimulation to the auricular branch of the vagus nerve, according to an embodiment of the present disclosure.

[0091] [Figure 16] FIG. 1 illustrates an algorithm for determining a person's current respiratory phase and when the respiratory phase begins or ends, according to an embodiment of the present disclosure. [Figure 17] FIG. 1 illustrates an algorithm for determining a person's current respiratory phase and when the respiratory phase begins or ends, according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0092] Various features and advantages of the present disclosure will now be described with reference to the accompanying drawings. The following description is merely exemplary in nature and is in no way intended to limit the present disclosure, its application, or uses. The present disclosure extends beyond the specifically disclosed embodiments and / or uses, as well as obvious modifications and equivalents thereof. Therefore, it is intended that the scope of the present disclosure should not be limited by any particular embodiment described below. Features of the illustrated embodiments can be modified, combined, removed, and / or substituted.

[0093] Several disorders and conditions, including but not limited to postpartum depression and gastrointestinal issues in Parkinson's disease, can be treated with vagus nerve stimulation. Figure 1A shows an exemplary ear with various portions indicated in the text, including one or more of the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, helical crus, tragus, intertragal notch, earlobe, antitragus, and concha (e.g., the cavity of the concha and / or the navicular vessel). Due to the location of the vagus nerve's termination, in one embodiment, the appropriate region of the ear for stimulation is within the navicular vessel of the concha. Other locations, such as the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, helical crus, tragus, intertragal notch, earlobe, antitragus, and / or concha cavity, as well as combinations thereof, are also used in various embodiments. Vagus nerve modulation is achieved using a device described herein, according to some embodiments. In some embodiments, the device described herein is used to stimulate the autonomic nervous system. In some embodiments, the devices described herein are used to balance the sympathetic / parasympathetic nervous systems (e.g., by upregulating / downregulating / maintaining neural activity to achieve equilibrium). Some system embodiments utilize multiple elements to vary treatment to prevent habituation and / or adjust amplitude to manage discomfort. In one embodiment, varying frequency or other parameters reduces tolerance or habituation and / or increases patient comfort / compliance.

[0094] FIG. 1B shows two exemplary locations where a neuroeffector (e.g., an electrode) can be placed within the concha navicularis to deliver stimulation. In some embodiments, placement is provided in the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, helical crus, tragus, intertragal notch, ear lobe, antitragus, concha cavity, and / or concha navicularis, or a combination thereof. Some embodiments of the auricle devices discussed herein include electrodes (e.g., active and return electrodes) positioned in locations such as those shown in FIG. 1B. In one embodiment, the electrodes include stainless steel, which has low impedance but requires a gel for electrical coupling to the skin / tissue. In one embodiment, the electrodes include a substrate (e.g., silicone) and a conductive filler or filler material (e.g., carbon nanotubes (CNTs)). In some embodiments, the conductive filler material may include a powder or particulate material. The conductive filler material may include a metal, carbon, or a mixture thereof. In some embodiments, the conductive filler material may include single-walled carbon nanotubes (SWCNs). In some embodiments, the conductive filler material may include double-walled carbon nanotubes (DWCNs). In certain embodiments, filler materials in the form of CNTs do not require a coupling gel, but may have a high baseline impedance and rapidly degrade in performance with wear and use.

[0095] In one embodiment, shown in Figures 1C-1D and 1E-1F, the auricle device 100 includes an electrode 122 that includes a ring interface. In one embodiment, the width and thickness vary. In one embodiment, a prongless design is used.

[0096] In one embodiment, impedance decreases with greater pressure on the interface between the electrode and the skin / tissue. In one embodiment, optimal pressure impedance is achieved at a pressure of about 2-3 Newtons (N). In some embodiments, it is between 0.01 Newtons (N) and about 1 Newton (N) (e.g., 0.01-0.05 N, 0.05-0.05 N, 0.01-0.1 N, 0.1-0.5 N, 0.5-1 N, and overlapping ranges therein). In various embodiments, pressure impedance is achieved at a pressure of approximately 0.01 to 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 Newtons, and any value and range therein). In one embodiment, pressure is measured using an Arduino Nano with FSR, an HC-05 Bluetooth module with an Android app for viewing the device, as shown in Figures 1G, 1H, 1I, 1J, and 1K, to reveal an exponential regression calibration curve giving readings in Newtons. In various embodiments, as shown in FIGS. 1L-1M, the earpiece includes a pressure applicator 160 (e.g., a spring-loaded surface and other pressure application surfaces, e.g., gas pressure, fluid pressure, foam pressure, magnetic, or temperature-changing material pressure configurations) and various angles to reduce impedance between the electrode and tissue. In some embodiments, the ear device 100 can include a pressure applicator 160 configured to bias one or more electrodes in a direction toward the ear. The pressure applicator 160 can be configured to increase the level of pressure applied by the one or more electrodes against the ear to reduce impedance between the one or more electrodes and the ear. The pressure applicator 160 can be a spring-loaded surface. In various embodiments, the pressure applicator 160 includes a gas pressure, fluid pressure, foam pressure, magnetic, or temperature-changing material pressure configuration. In some embodiments, a neuromodulation system (including devices and components) is provided.The system may include an electrical stimulation pulse generator that delivers electrical stimulation pulses to an earpiece positioned inside the ear. The earpiece may include two electrodes protruding from an upper portion of a boot 165 that rests on the concha of the ear and stimulates the auricular branch of the vagus nerve, and a pressure applicator configured to urge at least one of the two electrodes toward the ear. In some embodiments, the boot 165 includes a housing having a material for placement on a portion of the skin. The boot 165 may be at least partially made of silicone and designed to rest at the entrance of the ear canal. In some examples, the pressure applicator may be configured to increase the level of pressure applied by at least one of the two electrodes against the ear to reduce impedance between at least one or more of the two electrodes and the ear. The pressure applicator 160 may be a spring-loaded actuation surface. In various embodiments, the pressure applicator 160 includes gas pressure, fluid pressure, foam pressure, magnetic, or temperature-changing material pressure configurations.

[0097] In one embodiment, a filled dry electrode includes a substrate and a filler material. The substrate can be composed of silicone or a silicone-like material such as fluorosilicone, although any other elastomer may be used. The filler material can be composed of carbon nanotubes or any other conductive metal nanowires. Other filler materials may be used instead of or in addition to these nanowires. The filler material can be filled to anywhere from 0-25% into the material matrix (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 may be within a 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.

[0098] In one embodiment, the electrode is configured to be a non-invasive neuromodulation device. In one embodiment, the electrode includes an elastomeric base that forms a matrix that can be filled with a filler material. In one embodiment, the dry electrode allows for long-term use for non-invasive peripheral nerve stimulation. In various embodiments, this material can be implemented in electrodes for wrist-worn and / or auricular devices.

[0099] In one embodiment, the dry electrode includes a substrate and a filler material. In one embodiment, the substrate may be one or more of silicone, fluorosilicone, or some other elastomer. In one embodiment, the filler material may be one or more of carbon nanotubes (CNTs), metal nanowires, or other filler materials. In one embodiment, the electrode has a thickness of at least 0.25 millimeters and at most 5 millimeters. In one embodiment, the electrode is self-wetting. In one embodiment, the filler material has a fill factor of 0% to 25%.

[0100] Various embodiments of the auricle devices discussed herein can include active and return electrodes positioned (e.g., center-to-center) from each other in any range bounded by, for example, about 5 mm to about 20 mm, e.g., about 6 mm to about 19 mm, about 7 mm to about 18 mm, about 8 mm to about 17 mm, about 9 mm to about 16 mm, about 10 mm to about 15 mm, about 11 mm to about 14 mm, about 12 mm to about 13 mm, or about 11 mm to about 12 mm, or any value therebetween, or any combination of these values, although values ​​outside these values ​​or ranges can also be used in some cases. As another example, various embodiments of the auricle devices discussed herein can include active and return electrodes positioned about 11.5 mm from each other. Such a configuration can advantageously maximize vagus nerve stimulation and accommodate large variations in ear anatomy and / or characteristics.

[0101] Various embodiments of the auricular devices discussed herein can include electrodes (e.g., active and return electrodes), each having an electrode-skin contact surface area diameter of about 1 mm to about 10 mm, e.g., about 2 mm to about 9 mm, about 3 mm to about 8 mm, about 4 mm to about 7 mm, about 5 mm to about 6 mm, about 3 mm to about 5 mm, about 2 mm to about 6 mm, or any value therebetween, or any range bounded by any combination of these values, although values ​​outside these values ​​or ranges can also be used in some cases. As another example, various embodiments of the auricular devices discussed herein can include electrodes, each having an electrode-skin contact surface area diameter of about 4 mm. Such a configuration can advantageously maximize vagus nerve stimulation and accommodate large variations in ear anatomy and / or characteristics.

[0102] Various embodiments of auricle devices discussed herein include a first portion that can be secured in and / or within (e.g., at least partially within) a user's ear canal and a second portion coupled to the first portion that can be positioned and / or positioned in close proximity to and / or adjacent to (e.g., adjacent to, in, or in contact with) the concha navicularis of the user's ear when the first portion is secured in and / or within the ear canal. Such a second portion can include a neuroeffector that can provide electrical neuromodulation (e.g., stimulation). As described elsewhere herein, the neuroeffector can be and / or include one or more, multiple, and / or at least one or at least two electrodes (e.g., an active electrode and a return electrode). Such a configuration of "linking" the first and second portions of the auricular device together (e.g., using a reference point in the ear canal) advantageously provides improved spatial understanding and proper placement of neuroeffectors near and / or adjacent (e.g., adjacent to, within, or in contact with) the concha navicularis, as the first portion can be utilized as a positioning and / or confirmation mechanism for placement of the auricular device. In some embodiments, placement adjacent the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, helical crus, tragus, intertragal notch, earlobe, antitragus, cavity of the concha, and / or navicularis, or combinations thereof, is provided.

[0103] The various embodiments of the ear devices discussed herein can be configured so as not to interfere with the user's ability to hear external sounds or to connect to personal audio.

[0104] 2A-2G show various views of an exemplary embodiment of an ear device 100. The ear device 100 can include a first portion that can be secured in and / or within (e.g., at least partially within) a user's ear canal, and a second portion coupled to the first portion that can be disposed and / or positioned proximate and / or adjacent (e.g., adjacent to, within, or in contact with) the concha navicularis of the user's ear when the first portion is secured in and / or within the ear canal. Such a first portion of the ear device 100 can be, for example, an ear canal element 110. The ear canal element 110 can be sized and / or shaped to fit within (or at least partially within) the user's ear canal. For example, the ear canal element 110 can include a narrowed and / or tapered tip that can facilitate insertion and / or securing within a portion of the ear canal. The ear canal element 110 can be, for example, similar to that adapted for use with an audio microphone (e.g., earphones) in some embodiments. In some embodiments, the ear canal element 110 is a customized 3D printed component that allows for a better fit to the user's ear canal. In some embodiments, the auricle device 100 is configured to allow various ear canal elements to be swapped and / or replaced to provide sizing flexibility. Such a second portion of the auricle device 100 can be and / or include one or more prongs, such as one or both of the prongs 120a, 120b. The prongs 120a, 120b can include and / or operably position one or more electrodes. For example, the auricle device 100 can include a first electrode 122a coupled to and / or positioned along the prong 120a and / or a second electrode 122b coupled to and / or positioned along the prong 120b (see FIG. 2C ). The first electrode 122a can be the active electrode and the second electrode 122b can be the return electrode, or vice versa.The first electrode 122a can be coupled to the end of the prong 120a, and / or the second electrode 122b can be coupled to the end of the prong 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.

[0105] The first and second portions of the ear device 100 described above can be coupled to one another. 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, a stem 130 and / or a boss 140 (described below). The stem 130 can be an elongated element (e.g., the stem 130 can have a length or height that is greater than one or more dimensions of the cross section of the stem 130). In some embodiments, the ear device 100 includes a boss 140 (which may also be referred to herein as a “coupler” or “adapter”) that can couple the first and / or second portions of the ear device 100 to one another, for example, along with the stem 130. For example, the ear device 100 can include a boss 140 that can couple (e.g., directly or indirectly) the ear canal element 110 to the stem 130, and thus couple the ear canal element 110 to the prong(s) 120a, 120b. In some embodiments, the boss 140 can be removably coupled to the stem 130. For example, in some embodiments, the boss 140 can be configured to secure to the stem 130 via a snap-fit ​​arrangement.

[0106] In some embodiments, the auricle device 100 includes a cable 150 that can facilitate an electrical connection between the electrical components of the auricle device 100 (e.g., the electrodes 122a, 122b of the auricle device 100) and a power source. Such a power source can be remote and / or separate from the auricle device 100. For example, the auricle device 100 can include a cable 150 that connects to a power source integrated into a housing or enclosure attached to a portion of the user (e.g., behind the ear, secured over the ear, in a headband secured around the user's head, around the user's neck, and / or around the user's arm). As another example, the auricle device 100 can include a cable 150 that connects to a power source integrated into a housing or enclosure attached to the upper arm of the user (e.g., a patient), which can also include a blood pressure cuff that can be used as a therapy sensor. In some embodiments, the auricle device 100 is configured to receive power via the cable 150, which can also be configured to facilitate audio delivery through the ear canal element 110. In some embodiments, the cable 150 is a 2.5 mm cable.

[0107] In some embodiments, the ear device 100 does not include a cable (such as cable 150). For example, in some embodiments, the ear device 100 includes a power source for providing power to the electrical components of the ear device 100 (e.g., the electrodes 122a, 122b of the ear device 100). For example, any of the ear canal element 110, the stem 130, the boss 140, and / or the prongs 120a, 120b may 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).

[0108] In some embodiments, the auris device 100 includes one or more sensors for calibration or for purposes of therapy delivery (e.g., closed-loop therapy delivery), including, but not limited to, a photoplethysmogram (PPG) sensor, a galvanic skin sensor (GSR), an inertial measurement unit (IMU) sensor, a temperature sensor, a respiration sensor, and an electroencephalography (EEG) sensor. In some embodiments, respiration is measured with mechanical, electrical, impedance, acoustic (e.g., microphone), ultrasonic, infrared, or video-based measures. Alternatively or additionally, any of such aforementioned sensors may be incorporated into a housing or enclosure separate and / or spaced apart from the auris device 100 as described above.

[0109] As discussed above, and with continued reference to FIGS. 2A-2G , the stem 130 can have a generally elongated shape. The stem 130 can include, among other things, a cylindrical shape. The stem 130 can include, for example, a circular cross-section. The stem 130 can include a first end that connects to and / or receives a portion of the cable 150 (e.g., if the auricle device 100 includes such a cable 150), and the stem 130 can include a second end that connects to the prongs 120 a, 120 b. In some embodiments, the stem 130 includes a hollow interior sized and / or shaped to receive the cable 150.

[0110] As described above, the ear device 100 can include one or more prongs, such as prongs 120a and 120b. In some embodiments, the ear device 100 includes both prongs 120a and 120b. Alternatively, in some embodiments, the ear device 100 includes only prong 120a or prong 120b. The prongs 120a and / or 120b can extend from a portion of the stem 130. For example, the prongs 120a and / or 120b can extend from an end of the stem 130. The prongs 120a and / or 120b can extend outward from each other from the stem 130. For example, each of the prongs 120a and 120b can have a first end connected to the stem 130 and a second end (which can be referred to as a "free" end) opposite the first end. The prongs 120a, 120b can extend from the stem 130 such that such second or free ends of the prongs 120a, 120b are spaced outwardly from one another. The prongs 120a, 120b can include, among other things, a cylindrical shape. The prongs 120a, 120b can include, for example, a hollow interior sized and / or shaped to receive the cable 150a, a portion thereof, or a cable coupled to the cable 150, which electrically connects the electrodes 122a, 122b to a power source. The prongs 120a, 120b can have, for example, a circular cross-section, among other things.

[0111] The ear device 100 can include one or more electrodes positioned at or near the free ends of the prongs 120 a, 120 b. For example, the ear device 100 can include an active electrode 122 a at the free end of the prong 120 a and a return electrode 122 b at the free end of the prong 120 b. In some embodiments, the free ends of the prongs 120 a, 120 b, and thus the electrodes 122 a, 122 b, are positioned a distance from each other, for example, about 5 mm to about 20 mm from each other. For example, the free ends of prongs 120a, 120b, and thus electrodes 122a, 122b, can be positioned in any range bounded by approximately 6 mm to approximately 19 mm, approximately 7 mm to approximately 18 mm, approximately 8 mm to approximately 17 mm, approximately 9 mm to approximately 16 mm, approximately 10 mm to approximately 15 mm, approximately 11 mm to approximately 14 mm, approximately 12 mm to approximately 13 mm, or approximately 11 mm to approximately 12 mm, or any value therebetween, or any combination of these values, although values ​​outside these values ​​or ranges can also be used in some cases. As another example, in some embodiments, the free ends of prongs 120a, 120b, and thus electrodes 122a, 122b, are positioned approximately 11.5 mm from each other. Such a configuration can advantageously maximize vagus nerve stimulation and accommodate large variations in ear anatomy and / or characteristics.

[0112] 2B-2C and 2F, prongs 120a, 120b can be angled relative to one another at an angle between about 5° and about 120°. For example, prongs 120a, 120b can be angled relative to one another at an angle 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 therein, or any combination of these values, although values ​​outside these values ​​or ranges can also be used in some cases.

[0113] In some embodiments, the diameter of the electrode-skin contact surface area of ​​each of electrodes 122a, 122b is about 1 mm to about 10 mm, e.g., about 2 mm to about 9 mm, about 3 mm to about 8 mm, about 4 mm to about 7 mm, about 5 mm to about 6 mm, about 3 mm to about 5 mm, about 2 mm to about 6 mm, or any value therebetween, or any range bounded by any combination of these values, although values ​​outside these values ​​or ranges can also be used in some cases. As another example, in some embodiments, the diameter of the electrode-skin contact surface area of ​​each of electrodes 122a, 122b is about 4 mm. Such a configuration can advantageously maximize vagus nerve stimulation and accommodate large variations in ear anatomy and / or characteristics.

[0114] In some embodiments, when the ear canal element 110 is at least partially secured within a user's ear canal, the prong(s) 120a, 120b are configured to exert a normal force of about 0.1 N to about 1 N in and / or on the concha fin. For example, such exerted normal force can be any range bounded by about 0.2 mm to about 0.9 mm, about 0.3 mm to about 0.8 mm, about 0.4 mm to about 0.7 mm, or about 0.5 mm to about 0.6 mm, or any combination of these values, although values ​​outside these values ​​or ranges can also be used in some cases. In some embodiments, exertion of normal force on the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, helical crus, tragus, intertragal notch, earlobe, antitragus, concha cavity, and / or concha fin, or a combination thereof, is provided.

[0115] In some embodiments, the pinna device 100 can be configured to allow the ear canal element 110 to move relative to the stem 130, and the stem can allow the ear canal element 110 and the prongs 120a, 120b (and / or electrodes 122a, 122b) to move relative to one another. Additionally or alternatively, in some embodiments, the pinna device 100 can be configured to allow the ear canal element 110 to rotate relative to the stem 130 and / or the prongs 120a, 120b and / or the electrodes 122a, 122b. For example, the pinna device 100 can include a boss 140 that can facilitate such movement and / or rotation.

[0116] 2H-2J show various views of the boss 140 and the ear canal element 110 without showing other components of the pinna device 100. 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 360° rotation relative to each other, or an amount or range of rotation less than 360°. The boss 140 can include a pocket 142 sized and / or shaped to receive and / or secure the stem 130 or a portion thereof. The pocket 142 can have, for example, a circular or partially circular cross-section (see FIG. 2I). The pocket 142 can be sized and / or shaped to surround all or a portion of the periphery of the cross-section of the stem 130. For example, the pocket 142 can be sized and / or shaped to encompass less than the entire circumference of the cross section of the stem 130. Such a configuration can allow the stem 130 to be inserted into the pocket 142 transversely (e.g., perpendicularly) to an axis extending through the pocket 142 and / or parallel to such an axis. The pocket 142 can allow the boss 140 and the stem 130 to move relative to one another (e.g., linearly or longitudinally) while they are coupled to one another. Thus, because the boss 140 and the stem 130 can be coupled to the ear canal element 110 and the prongs 120a, 120b, such relative movement between the boss 140 and the stem 130 can therefore allow the prongs 120a, 120b and the ear canal element 110 to move relative to one another. Such a configuration advantageously allows the auricle device 100 to be adjusted to accommodate a user's anatomy, such as a variable distance between the user's ear canal and the concha navicularis.

[0117] In some embodiments, the ear device 100 includes a mechanism that allows the boss 140 and stem 130 to be retained or removably secured in a particular position. For example, the boss 140 may include a protrusion 144 that can interact with one or more notches 132 in the stem 130 to facilitate adjustment of the boss 140 and stem 130 in various positions. In some embodiments, the protrusion 144 may be positioned within the pocket 142. For example, in some embodiments, the protrusion 144 is disposed at or near the center of the pocket 142 and / or extends outward from a surface of the pocket 142. The protrusion 144 may be rounded, e.g., have a semicircular or arched shape. The notch 132 may be recessed from the outer surface of the stem 130 and may 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 evenly or unevenly spaced from one another 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 boss 140 (described elsewhere herein) can be disposable, while the stem 130, prongs 120a, 120b, and / or cable 150 are reusable.

[0118] 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.

[0119] The above-described features that can allow the boss 140 and stem 130 (and thus the ear canal element 110 and prongs 120a, 120b, electrodes 122a, 122b) to move and / or rotate relative to one another advantageously allow the auricle device 100 to provide a "one-size-fits-all" solution to accommodate large variations in ear anatomies or characteristics when providing electrical neuromodulation (e.g., stimulation) to the vagus nerve via the concha navicularis.

[0120] The stem 130, boss 140, prongs 120a, 120b, and / or ear canal element 110 can comprise, partially or entirely, plastic. Alternatively or additionally, the stem 130, boss 140, prongs 120a, 120b, and / or ear canal element 110 can comprise, partially or entirely, silicone, a silicone-like material, such as fluorosilicone, or other elastomer.

[0121] As discussed elsewhere herein, the pinna device 100 can include prongs 120a, 120b, each of which can include and / or be operatively positioned at or adjacent to the concha of the subject's ear. In some embodiments, one or both of such prongs 120a, 120b are flexible and / or resilient. One or both of such prongs 120a, 120b can be independently flexible, for example, relative to each other and / or other portions of the pinna device 100 (e.g., the ear canal element 110 and / or the stem 130). One or both of such prongs 120a, 120b can be configured to allow each of the active electrode 122a and the return electrode 122b (described herein) to simultaneously and independently contact a portion of the concha. One or both of such prongs 120a, 120b can be configured to enable each of the active electrode 122a and the return electrode 122b (discussed herein) to simultaneously apply a force (e.g., a normal force) of between about 0.01 N and about 1 N or other values, e.g., for forces discussed elsewhere herein, to a portion of the concha. Such normal force(s) can be applied, for example, when the ear canal element 110 is secured within the user's ear canal. Such a configuration can advantageously enable the prongs 120a, 120b to provide independent suspension (e.g., when engaging the subject's ear with the ear canal element 110) that can enable each electrode coupled to the prongs 120a, 120b to independently contact the concha in a comfortable manner without applying excessive force and / or pressure. Such a configuration can therefore reduce or eliminate the possibility that contact between an electrode coupled to prong 120a and the navicularis concha will interfere with contact between an electrode coupled to prong 120b and the navicularis concha. Any of the prongs of any of the other auricle devices discussed herein may be flexible and / or resilient as described above with respect to prongs 120a, 120b.

[0122] 3 shows another embodiment of an ear device 200. The ear device 200 may be similar in some or many respects to the ear device 100. For example, the ear device 200 may include an ear canal element 210, a stem 230, a boss 240, prong(s) 220a, 220b, and / or a cable 250, each of which may be similar to or identical to the ear canal element 110, the stem 130, the boss 140, the prong(s) 120a, 120b, and / or the cable 150 described above with reference to the ear device 100. The prongs 220a, 220b may include electrodes similar to or identical to the electrodes 122a, 122b described above, for example, disposed at the free ends of the prongs 220a, 220b.

[0123] 3 , 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 another portion of the stem 230 (e.g., on opposite sides or portions of the stem 230). Such notches can be identical to the notches 132 described above with respect to the stem 130. The indicators 235 can advantageously indicate to the user where the respective notches on the stem 230 are located to help the user adjust the distance and / or location of the boss 240 and / or ear canal element 210 relative to the stem 230, the prongs 220 a, 220 b, and / or the electrodes associated with the prongs 220 a, 220 b. The stem 230 can include one, two, three, four, five, six, seven, or eight or more indicators 235, and such indicators 235 can be evenly or unevenly spaced from another notch along the length of the stem 230. Such an indicator 235 may be, for example, a line extending across the surface of the stem 230 .

[0124] As shown in FIG. 3 , the stem 230 can be curved, for example, curved between opposing ends of the stem 230. However, in alternative embodiments, 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 prongs 220 a, 220 b, and / or the ear canal element 210 can comprise, partially or entirely, plastic. Alternatively or additionally, the stem 230, the boss 240, the prongs 220 a, 220 b, and / or the ear canal element 210 can comprise, partially or entirely, silicone. In some embodiments, the stem 230 comprises silicone and the boss 240 comprises plastic (e.g., hard plastic).

[0125] 4 shows bosses 240′, 240″, 240′″ that can be associated with three different sizes and / or configurations of pinna device 200 (or any of the pinna devices discussed herein), each size including a locking position for stem 230 such that rotational and axial / linear movement of stem 230 is fixed. For example, each of these three sizes can be associated with a fixed rotational and axial / linear position of stem 230. Such a configuration can ensure, for example, that the stem of the pinna device is rotated and / or extended at the correct or optimal angle relative to the ear canal elements.

[0126] 5A-5B show another embodiment of an ear device 300. The ear device 300 may be similar in some or many respects to the ear device 100 (and / or other ear devices discussed herein). For example, the ear device 300 may include an ear canal element 310, a stem 330, and prong(s) 320a, 320b, each of which may be similar or identical to the ear canal element 110, the stem 130, and / or the prong(s) 120a, 120b described above with reference to the ear device 100. Like the stem 230, the stem 330 may be curved, for example, along all or a portion of its length (e.g., less than half of its length). The prongs 320a, 320b may extend from the stem 330 and may be angled, for example, at an angle such as any of the angles described above with respect to the prongs 120a, 120b. In one embodiment, prongs 320a, 320b are angled at approximately 90° relative to one another (e.g., 70°-80°, 80°-90°, 90°-100°, and overlapping ranges therein). Prong 320a can form and / or be part of the extension of stem 330, e.g., can extend along the same path of stem 330.

[0127] 5C and 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 prongs 320a, 320b in a superior and / or anterior position adjacent the navicularis. In some embodiments, the ear canal element 310 can be manufactured separately from the stem 330 and / or the prongs 320a, 320b.

[0128] 6A-6B show another embodiment of an ear pinna device 400. The ear pinna device 400 may include an ear canal element 410 that can be secured to and / or within (e.g., at least partially within) a 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 is sized and / or shaped to receive the wire element 430 and may include one or more openings (e.g., holes) configured to allow the boss 440 to move relative to the wire element 430, for example, along the length of the wire element 430. Such a configuration may allow the ear canal element 410 to move relative to the wire element 430 when the boss 440 is coupled with the ear canal element 410. The wire element 430 may include one or more electrodes, such as electrodes 422a, 422b. The electrodes 422a, 422b may be active and return electrodes. The electrodes 422a, 422b can be positioned along a portion of the wire element 430 that is defined and / or segmented by coupling with the boss 440 and / or opening (e.g., hole) in the boss 440 that receives the wire element 430. The length and / or size of such defined and / or segmented portion of the wire element 430 that includes the electrodes 422a, 422b can be adjusted, for example, by moving the boss 440 along the wire element 430. Such a configuration can advantageously allow the defined and / or segmented portion of the wire element 430 to be tailored to the size and / or shape of a given user's concha navicularis. In some embodiments, one or more clips or other attachment / coupling devices are used to couple the neuromodulation device to the ear. In some embodiments, earphones are used. In some embodiments, vibration therapy is included.

[0129] The electrodes 422a, 422b can be pre-mounted or overmolded to the wire element 430. The electrodes 422a, 422b can be fixed on the wire element 430 or can be configured to move along the wire element 430. The electrodes 422a, 422b can be spaced apart from one another along the wire element 430 by a distance 425 that can be the same as the distance described above with respect to the electrodes 122a, 122b (e.g., about 10-14 mm, e.g., 11.5 mm).

[0130] FIG. 7 shows another embodiment of an ear device 400′ that may be identical to the ear device 400, except that it includes a positioning indicator 480′ and a separate component 470′ that includes electrodes 422a, 422b with a predefined spacing (e.g., the distance described above for electrodes 122a, 122b) that can be coupled to the wire element 430 according to the indicator 480′. The indicator 480′ can be printed, for example, on the wire element 430. Alignment of a portion of the separate component 470′ with one or more of the positioning indicators 480′ can facilitate small, medium, or large “sizing” for the user. Such separate component 470′ can be adjustable by the user or can be locked in place and / or can be pre-threaded onto the wire element 430 or configured to clip onto the wire element 430.

[0131] Neuromodulation Devices FIG. 8A shows a block diagram of an exemplary neuromodulation (e.g., neurostimulation) device 800. In some embodiments, the features described with reference to the neuromodulation device 800 can form part of and / or be incorporated into any of the auricle devices described herein that can be placed in or adjacent to a user's ear. However, the features discussed with reference to the neuromodulation device 800 are not so limited and can be incorporated into other types of neuromodulation devices. The device 800 includes multiple hardware components capable of, or programmed to, provide therapy across the user's skin. As shown in FIG. 8A, some of these hardware components may be optional, as indicated by dashed blocks. In some cases, the device 800 may include only the hardware components necessary for stimulation therapy. The hardware components are described in more detail below.

[0132] Device 800 can include two or more effectors, for example, electrodes 802 for providing neural stimulation signals. In some cases, device 800 is configured for transcutaneous use only and does not include 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 to the skin to improve conductance. In some embodiments, the electrodes do not include any hydrogel material, adhesives, or the like. In one embodiment, one or more implantable component(s) are provided.

[0133] The device 800 may further include a stimulation circuit 804 for generating a signal applied via the electrode(s) 802. The signal may vary in frequency, phase, timing, amplitude, or offset. The device 800 may also include power electronics 806 for powering the hardware components. For example, the power electronics 806 may include a battery.

[0134] The device 800 can include one or more hardware processors 808. The hardware processors 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 of the processing described herein is performed by the hardware processor(s) 808. The memory 810 can store patient-specific data and operating rules, as described below.

[0135] In the depicted illustration, device 800 may include one or more sensors 812. As shown, the sensor(s) 812 may be optional. The sensors may include, for example, biomechanical sensors configured to measure movement, respiration, and / or bioelectric sensors (e.g., EMG, EEG, and / or nerve conduction sensors). The sensors may include, for example, cardiac activity sensors (e.g., ECG, PPG), skin conductance sensors (e.g., galvanic skin response, electrodermal activity), respiration sensors (e.g., respiratory effort belt, acoustic, microphone), and motion sensors (e.g., accelerometer, gyroscope), as well as combinations thereof. One or more sensors 102 may include an inertial measurement unit (IMU).

[0136] In some embodiments, the IMU can include one or more of a gyroscope, an accelerometer, and a magnetometer. The IMU can be attached to or integrated into the neuromodulation (e.g., neurostimulation) device 800. In one embodiment, the IMU is an off-the-shelf component. In addition to its usual meaning, the IMU can also include specific components, as described 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 in multiple axes. Furthermore, the IMU can also include one or more gyroscopes and / or magnetometers in additional embodiments. Because the IMU can be integrated with the neurostimulation device 800, the IMU can generate data from its sensors in response to motion, movement, or vibration sensed by the device 800. Furthermore, when the device 800 with an integrated IMU is worn by a user, the IMU can enable detection of the user's voluntary and / or involuntary movement.

[0137] The device 800 may optionally include user interface components such as a feedback generator 814 and a display 816. The display 816 may provide instructions or information to the user regarding calibration or therapy. The display 816 may also provide alerts, such as instructions for responding to therapy. Alerts may also be provided using the feedback generator 814, which may provide tactile feedback to the user at the start or end of stimulation, for reminder alerts, to alert the user to troubleshooting conditions, among other things. Thus, the user interface components such as the feedback generator 814 and the display 816 may provide audio, visual, and tactile feedback to the user.

[0138] Additionally, device 800 may include communications hardware 818 for wireless or wired communications between device 800 and external systems, such as user interface devices described below. The communications hardware 818 may include an antenna. The communications hardware 818 may also include an Ethernet or data bus interface for wired communications.

[0139] While the illustrated diagram shows several components of device 800, some of these components are optional and not required in all embodiments of device 800. In some embodiments, the system may include a diagnostic device or component that does not include neuromodulation functionality. The diagnostic device may be a companion wearable device that is wirelessly connected via a connected cloud server and may include sensors such as cardiac activity, skin conductance, respiration, and / or movement sensors as described elsewhere herein.

[0140] In some embodiments, device 800 can also be configured to deliver one, two, or more of magnetic, vibration, mechanical, thermal, ultrasonic, or other forms of stimulation instead of, or in addition to, electrical stimulation. Such stimulation can be delivered via one, two, or more effectors in contact with or in proximity 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, vibration, mechanical, thermal, ultrasonic, or other forms of stimulation.

[0141] While several neurostimulation devices are described herein, in some embodiments, nerves are non-invasively modulated to achieve neural inhibition. Neural inhibition can be achieved in a variety of ways, including, but not limited to, hyperpolarizing neurons to inhibit action potentials and / or depleting ionic stores in neurons to inhibit firing action potentials. This can be achieved, in some embodiments, through the generation of neural excitation or neural inhibition. For example, anodal or cathodal stimulation, low-frequency stimulation (e.g., below about 5 Hz in some cases), or continuous or intermediate burst stimulation (e.g., theta burst stimulation) can be implemented. In some embodiments, the wearable device has at least one implantable portion, which may be temporary or longer-term. In many embodiments, the device is entirely 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 is applied at frequencies between 1 Hz and 10 Hz (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 Hz, and 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, 2-7, 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).

[0142] Any of the auricular devices discussed herein can be used to treat several diseases and conditions, including, but not limited to, depression, such as depression associated with Parkinson's disease and / or postpartum; gastrointestinal issues, such as gastrointestinal issues associated with Parkinson's disease and / or postpartum; 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; migraines; addiction; stress; and tinnitus, among others. In some embodiments, immune dysfunction is treated. In some embodiments, the auricular 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 neuromodulation devices.

[0143] In some examples, neuromodulation, such as neurostimulation, can provide therapeutic benefits across 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), urinary system disorders, gastrointestinal disorders, cardiac 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 some embodiments. In one embodiment, cardiac conditions (such as atrial fibrillation, high blood pressure, and stroke) are treated. Epilepsy and other seizure disorders are treated in one embodiment. In some embodiments, inflammatory skin conditions and immune dysfunction are also treated.Other disorders can also be treated.For example, vagus nerve stimulation has been shown to improve hypertension symptoms, dexterity, and cardiac arrhythmias.

[0144] In one embodiment, a method framework for treating rheumatoid arthritis, atrial fibrillation, or migraine using peripheral nerve stimulation includes multiple treatment pathways: (a) an acute relief pathway, and / or (b) a preventative therapy pathway. In one embodiment, the treatment framework and each treatment pathway can be implemented by applying peripheral nerve stimulation via a wrist-worn neuromodulation device, an auricular neuromodulation device, or any combination of a wrist-worn device and an auricular device. One or both ears and / or wrists can be stimulated.

[0145] As used herein, a "prophylactic therapy pathway" or "preventing" is intended to include the alleviation of full-blown symptoms associated with a particular disease or condition. For example, a user may activate neurostimulation at the onset of mild symptoms, thereby preventing (or halting or reducing) the occurrence of further symptoms. As a non-limiting example, upon experiencing prodromal (pre-headache) symptoms, the use of neurostimulation described herein is used to prevent the occurrence of other, more severe symptoms. For example, in some embodiments, neurostimulation applied to a user as part of a prophylactic therapy reduces the likelihood that the user will develop symptoms that cause the user to change their treatment protocol to an acute relief pathway. In one embodiment, a prophylactic therapy pathway halts or reduces more severe symptoms by 50-95% (e.g., by more than 70%, 80%, 90%, etc.).

[0146] 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), movement and balance dysfunction, pain, and other neurological conditions. Disorders include, but are not limited to, tetanus, meningitis, Lyme disease, urinary tract infections, mononucleosis, chronic fatigue syndrome, autoimmune disorders, and the like. In some embodiments, autoimmune disorders and / or pain unrelated to microbial infection are treated, including, for example, inflammation, headache, back pain, joint pain and stiffness, muscle pain and tension, and the like.

[0147] Bradykinesia, dyskinesia, gait dysfunction, dystonia and / or rigidity may also be treated according to some embodiments.

[0148] The devices, systems, and methods described herein, in some embodiments, are used to treat Lyme disease (e.g., its associated symptoms). In one embodiment, inflammation associated with Lyme disease is reduced (e.g., including long-term or chronic inflammation and / or flare-ups). 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 associated symptoms, such as chronic inflammation, flare-ups, etc., are treated according to some embodiments. Treatment may be achieved, for example, by vagus nerve stimulation and / or sympathetic / parasympathetic balance. In some embodiments, the vagus nerve, trigeminal nerve, and / or greater auricular nerve are neuromodulated. In some embodiments, only the vagus nerve (e.g., auricular branch and / or non-auricular branch) is neuromodulated. In some embodiments, the vagus nerve (e.g., auricular branch and / or non-auricular branch) and one, two, or more other nerves are neuromodulated (e.g., the trigeminal nerve, the greater auricular nerve, the auricular branch, etc.). In some embodiments, the vagus nerve (e.g., auricular branch and / or non-auricular branch) is not stimulated, and instead, for example, one or more other nerves are stimulated (e.g., the trigeminal nerve, the greater auricular nerve, other nerves in the auricular branch, etc.). For example, the auricular branch of the vagus nerve may be stimulated, but other portions of the vagus nerve are not stimulated. In another embodiment, the auricular branch of the vagus nerve is stimulated before, after, or during stimulation of a non-auricular portion of the vagus nerve (or a non-vagus nerve). Neuromodulation according to some embodiments includes, for example, stimulation using parameters disclosed herein.

[0149] In one embodiment, a second therapy (e.g., vibration therapy) is provided in conjunction with the neurostimulation disclosed herein. The second therapy may be at a lower or higher frequency than the first stimulator and may include, for example, ultrasonic neuroeffector(s), such as piezoelectric elements. In some embodiments, the effector may be a phased array ultrasound (e.g., focused ultrasound) effector. For example, a phased array ultrasound effector may comprise a plurality of ultrasound transducer elements. Each element may have a width and a thickness. The thickness may be related to the width (e.g., the thickness may be a fraction (e.g., ½, ⅓, ¼, ⅕, ⅙, a range between such values, etc.) or a multiple (e.g., 2×, 3×, 4×, 5×, 10×, a range between such values, etc.) of the width). Each element may have a width, and the spacing between elements may be related to the width (e.g., the same as the width, half the width, twice the width). The spacing between elements may be adjustable. In some embodiments, the elements have a width of about 0.5 mm to about 2 mm and a spacing of about 0.1 mm to about 2 mm. The elements may be arranged in a one-dimensional array or a two-dimensional array. The elements may be cuboid, rectangular, cylindrical, prismatic, pyramidal, or any suitable shape. The ultrasound signal may be, for example, about 20 kHz to 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, ranges between such values, etc.). At least one of the elements may transmit a different frequency. Each element may transmit a different frequency. Each element may transmit the same frequency. In some embodiments, the dose level applied by the ultrasound effector is about 0 W / cm. 2 ~about 2W / cm 2 (For example, about 0 W / cm 2 , about 0.1W / cm 2 , about 0.25W / cm 2 , about 0.5W / cm 2 , about 1W / cm 2 , about 1.5W / cm 2 , about 2W / cm 2, ranges between such values, etc. One, some, or all of the ultrasound transducer elements may be diverging, focusing, scattering, flat, etc. In some embodiments, the transducer elements may be arranged to focus energy (e.g., energy from different elements results in constructive interference) at a location below the surface of the skin proximate to the target nerve or tissue region. In one embodiment, ultrasound therapy is used alone for auricle treatment.

[0150] Neuromodulation (e.g., neurostimulation) in some embodiments is used to replace pharmaceuticals, thus reducing undesirable drug side effects. In other embodiments, neuromodulation such as neurostimulation is used in conjunction with (e.g., synergistically with) pharmaceuticals, for example, to reduce the dose or duration of drug therapy, thereby reducing undesirable side effects. Undesirable drug side effects include, for example, addiction, tolerance, dependence, GI problems, nausea, confusion, dyskinesia, appetite changes, and the like. In various embodiments, neuromodulation such as neurostimulation is used in conjunction with (e.g., synergistically with) pharmaceuticals for the treatment of inflammatory conditions such as epilepsy, depression, anxiety, inflammatory bowel disease (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, chronic fatigue syndrome, and in some embodiments, other inflammatory conditions (such as neuroinflammatory and inflammatory skin conditions) are treated. Neuromodulation such as neurostimulation is used in conjunction with (e.g., synergistically with) pharmaceuticals for the treatment of cardiac conditions (such as atrial fibrillation, high blood pressure, and stroke), and in various embodiments, treatment. Seizure disorders are treated in one embodiment. Neuromodulation, such as neurostimulation, is used in conjunction with (e.g., synergistically with) pharmaceutical agents to treat headaches, such as migraines, in another embodiment.

[0151] User Interface Devices FIG. 8B shows communication between the neurostimulation device 800 and the user interface device 850 via a communication link 830. The communication link 830 may be wired or wireless. The neuromodulation (e.g., neurostimulation) device 800 can communicate with and receive 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, a smart watch, a tablet, or a wearable computer. The user interface device 850 can also include a server computing system remote from the neurostimulation device. The user interface device 850 can include hardware processor(s) 852, 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 those described elsewhere herein. Additionally, in some cases, the user interface device 850 can generate an alert in response to a device problem or a response to a therapy. The alert may be received from the neurostimulation device 800.

[0152] In additional embodiments, data obtained from one or more sensors 802 is processed by a combination of hardware processor(s) 808 and hardware processor(s) 852. In further embodiments, data collected from one or more sensors 802 is transmitted to user interface device 850 with little or no processing by hardware processor 808. In some embodiments, user interface device 850 may include a remote server that processes the data and sends a signal back to device 800 (e.g., via the cloud).

[0153] In some cases, the user interface device may be replaced by or operate in conjunction with a base station, which may be configured to periodically, e.g., daily, stream motion sensor and usage data and charge the device.

[0154] 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 greater auricular nerve, the auriculotemporal nerve, and / or the lesser occipital nerve, among others. In some embodiments, stimulation may alternate between each nerve so that nerves are not stimulated simultaneously. In some embodiments, all nerves (e.g., target nerves) are stimulated simultaneously. In some embodiments, stimulation is delivered to various nerves in one of a number of burst patterns. Stimulation parameters may include one, two, three, or more of on / off, duration, intensity, pulse rate, pulse width, waveform shape, and pulse rise and fall. In one embodiment, the pulse rate may be between about 1 Hz and about 100 Hz, about 1 Hz and about 5000 Hz, about 1 Hz and about 500 Hz, about 5 Hz and about 50 Hz, about 50 Hz and about 300 Hz, or about 150 Hz. In some embodiments, the pulse rate may be between 1 kHz and 20 kHz. The pulse width may range from 50 to 500 μs (microseconds), such as approximately 300 μs. The intensity of the electrical stimulation may vary from 0 mA to 500 mA, and the current may range from approximately 1 mA to 11 mA. As another example, the current may range from approximately 1 mA to approximately 5 mA. The electrical stimulation may be adjusted for different electrical stimulation methods in different patients. The intensity adjustment increments may be, for example, 0.1 mA to 1.0 mA. In one embodiment, the stimulation may last for approximately 10 minutes to 1 hour, such as approximately 10, 20, 30, 40, 50, or 60 minutes, or a range including any two of the foregoing values. In some embodiments, multiple electrical stimulations may be delivered offset in time from one another by a predetermined fraction of the period of a measured rhythmic biosignal, such as hand tremor, such as approximately 1 / 4, 1 / 2, or 3 / 4 of the period of the measured signal. In some embodiments, the multiple electrical stimuli can be delivered offset in time from one another by a predetermined percentage during the measured exhalation or measured inhalation (e.g., only during the measured exhalation or only during the measured inhalation).Further possible stimulation parameters are described, for example, in U.S. Pat. No. 9,452,287 to Rosenbluth et al., U.S. Pat. No. 9,802,041 to Wong et al., International Publication No. WO 2016 / 201366 to Wong et al., International Publication No. WO 2017 / 132067 to Wong et al., International Publication No. WO 2017 / 023864 to Hamner et al., International Publication No. WO 2017 / 053847 to Hamner et al., International Publication No. WO 2018 / 009680 to Wong et al., and application PCT / US2022 / 074376, now published as International Publication No. WO 2018 / 039458 to Rosenbluth et al. and International Publication No. WO 2023 / 015158 to Schulte et al., each of which is incorporated by reference in its entirety into this disclosure.

[0155] controller FIG. 8C shows a block diagram of one embodiment of a controller 880 that can be implemented using the hardware components described above with respect to FIGS. 8A-8B. The controller 880 can include multiple engines for performing the processes and functions described herein. The engines can include programmed instructions for implementing processes as discussed herein for detecting input conditions and controlling output conditions. The engines can be executed by one or more hardware processors of the neuromodulation (e.g., neurostimulation) device 800, alone or in combination with the user interface device 850. The programming instructions can be stored in memory 810. The programming instructions can be implemented in C, C++, JAVA, or any other suitable programming language. In some embodiments, some or all of the portions of the controller 880, including the engines, can be implemented in application-specific circuits such as ASICs and FPGAs. Some aspects of the functionality of the controller 880 can be performed remotely on a server (not shown) over a network. Although shown as separate engines, the functionality of the engines described below need not necessarily be separate. Thus, the controller 880 can be implemented using the hardware components described above with respect to FIGS. 8A-8B.

[0156] The controller 880 may include a signal collection engine 802. The signal collection engine 802 may enable acquisition of raw data from sensors built into the device, including, but not limited to, accelerometer or gyroscope data from an IMU 802. In some embodiments, the signal collection engine 802 may also perform signal pre-processing on the raw data. The signal pre-processing may include noise filtering, smoothing, averaging, and other signal pre-processing techniques to clean the raw data. In some embodiments, a portion of the signal may be discarded by the signal collection engine 802.

[0157] The controller 880 may also include a feature extraction engine 804. The feature extraction engine 804 may extract relevant features from the signals collected by the signal collection engine 802. The features may be in the time domain and / or the frequency domain. For example, some of the features may include amplitude, bandwidth, area under the curve (e.g., power), energy in a frequency bin, peak frequency, ratio between frequency bands, etc. The features may be extracted using signal processing techniques such as Fourier transform, band-pass filtering, low-pass filtering, high-pass filtering, etc.

[0158] The controller may further include a rule generation engine 806. The rule generation engine 806 may use features extracted from the collected signals to determine rules corresponding to neural stimulation therapy. The rule generation engine 806 may automatically determine correlations between particular extracted features and the results of the neural stimulation therapy. In some cases, features are extracted from biosignals sensed by one or more sensors and / or neural effectors (such as one, two, four, or six stimulation electrodes). In some embodiments, the stimulation electrodes themselves are utilized as sensing elements (e.g., to detect electrodermal activity, cardiac activity, or EEG) and may be positioned on or near the subject's ear or on or near a different part of the subject's body (such as the wrist, fingers, or part of the arm). The one or more sensors can be selected from a group including or consisting essentially of a photoplethysmography (PPG) sensor, a galvanic skin sensor (GSR), an inertial measurement unit (IMU) sensor, a temperature sensor (e.g., for body / skin temperature or ambient temperature), a respiration sensor (e.g., acoustic, microphone, etc.), and / or an electroencephalography (EEG) sensor (or a combination of two or more thereof). In some embodiments, features extracted from biosignals include movement data, electrocardiogram, or plethysmograph signals. The rule generation engine 806 can determine stimulation patterns to improve treatment outcomes.Results can include, for example, identifying patients who will respond to treatment based on characteristics of the kinematic data (e.g., approximate entropy) (e.g., during an initial trial fitting or calibration process), predicting stimulation settings for a given patient (based on characteristics of the patient's condition) that will result in the best treatment effect (e.g., where dosage, treatment dose or administration parameters include, but are not limited to, duration of stimulation, frequency and / or amplitude of the stimulation waveform, and time of day that stimulation is applied), predicting patient condition severity at a given time point, predicting patient response over time, examining patient medication responsiveness in combination with condition severity over time, predicting response to epicutaneous or penetrative stimulation, or other neurostimulation or neurosurgical procedures based on condition characteristics and severity over time, and predicting the ideal time for a patient to receive epicutaneous or penetrative stimulation, or deep brain stimulation or thalamotomy, based on condition characteristics and severity over time, or predicting patient-reported treatment outcomes or user-reported satisfaction using kinematic measurements from a device, predicting patient response to an undesirable user experience using condition features evaluated from baseline values ​​and patient usage logs, where undesirable user experiences may include, but are not limited to, device malfunctions and adverse events such as skin irritation or burns; predicting patient response trends based on condition severity, where trends can be evaluated across a total number of sessions, within a user, or across a population of users; predicting or classifying subtypes to predict user response based on kinematic analysis of condition features; predicting or classifying subtypes to provide guidance for individually optimized treatment parameters; predicting or classifying subtypes to optimize future study designs based on subtypes (e.g., selecting specific subtypes for clinical trials with specific designs that address treatment needs for the subtype); and predicting user or customer satisfaction (e.g., net promoter score) based on user response or other kinematic features from measured movement.In some embodiments, different administration schedules and / or different stimulation parameters can reduce tolerance or habituation and / or increase user comfort / compliance.

[0159] Symptoms include, but are not limited to, tremors, such as essential tremor. In one embodiment, with respect to tremor, the results may include identifying patients who will respond to treatment based on the tremor characteristics of the kinematic data (e.g., during an initial trial fitting or calibration process), predicting a given patient's stimulation settings (based on the patient's tremor characteristics) that will result in the best treatment effect (e.g., where dosage, treatment dose or administration parameters include, but are not limited to, duration of stimulation, frequency and / or amplitude of the stimulation waveform, and time of day the stimulation is applied), predicting patient tremor severity at a given time point, predicting patient response over time, examining patient medication responsiveness in combination with tremor severity over time, predicting response to epicutaneous or penetrative stimulation, or other neurostimulation or neurosurgical procedures based on tremor characteristics and severity over time, and predicting the ideal time for a patient to undergo epicutaneous or penetrative stimulation, or deep brain stimulation or thalamotomy based on tremor characteristics and severity over time, or using kinematic measurements from the device to measure patient-reported treatment outcomes or user-reported satisfaction. predicting patient response to an undesirable user experience using tremor features assessed from kinematic measurements and patient usage logs, where undesirable user experiences may include, but are not limited to, device malfunctions and adverse events such as skin irritation or burns; predicting patient response trends based on tremor severity, where trends can be assessed across a total number of sessions, within a user, or across a population of users; predicting patient response trends; predicting or classifying tremor subtypes to predict user response based on kinematic analysis of tremor features; 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 subtype (e.g., selecting specific subtypes of intrinsic tremor for clinical trials with specific designs that address treatment needs for the subtype); and based on user responses or other kinematic features from baseline tremor movements.This can include predicting user or customer satisfaction (e.g., net promoter score). In some embodiments, different administration schedules and / or different stimulation parameters can reduce tolerance or habituation and / or increase user comfort / compliance. Neuromodulation (e.g., auricular, wrist, leg neurostimulation) devices, in some embodiments, are used to identify patients who may be candidates for other treatments, such as drug therapy, surgical intervention, deep brain stimulation, or thalamotomy. Response and tolerance to the neurostimulation described herein, in some embodiments, is used to provide input to predictive models that provide an assessment of a patient's likelihood of responding to implantable deep brain stimulation or other implantable or non-implantable treatments. Algorithms and sensor measurements from the described devices can help identify patients who may be good or poor candidates for other treatments, such as deep brain stimulation, drug therapy, surgical intervention, or thalamotomy. In some embodiments, the devices described herein can be used to categorize subjects who use the device for one week to one year or longer into the top or bottom 50%, 25%, or 10% of subjects who respond to other such treatments. This can be particularly useful, so that patients who receive the majority of such treatments (such as deep brain stimulation) can benefit from this treatment. This type of predictive diagnostic capability, in some embodiments, leads to more personalized treatments and better health outcomes.

[0160] 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 utilize machine learning modeling along with signal processing techniques to determine the rules, including, but not limited to, supervised and unsupervised algorithms for regression and classification. Specific classes of algorithms include, for example, artificial neural networks (perceptrons, backpropagation, convolutional neural networks, recurrent neural networks, long-short-term memory networks, deep belief networks), Bayesian (naive Bayes, multinomial Bayes, and Bayesian networks), clustering (k-means, expectation-maximization, and hierarchical clustering), ensemble methods (classification and regression tree variants and boosting), instance-based (k-nearest neighbors, self-organizing maps, and support vector machines), regularization (elastic nets, ridge regression, and least absolute shrinkage and selection operators), and dimensionality reduction (principal component analysis variants, multidimensional scaling, discriminant analysis variants, and factor analysis). In some embodiments, the controller 886 can use the rules to automatically determine outcomes. The controller 886 can also use rules to control or change settings of the neurostimulator device, including, but not limited to, stimulation parameters (e.g., stimulation amplitude, frequency, patterning (e.g., burst stimulation), interval, time of day, individual session or cumulative time, etc.) as described below. In some cases, the rules may be hard-coded and do not need to be generated.

[0161] Thus, the rules can improve the operation of the neuromodulation device, e.g., neurostimulation device, and advantageously improve patient comfort. The generated rules can be stored in memory 810 and / or memory 854. For example, the rules can be generated after calibration and stored before operation of the neurostimulation device 800. Thus, in some embodiments, the rule application engine 888 can apply the stored rules to new data collected by the IMU or physiological sensor(s) to determine results or control the neuromodulation, e.g., neurostimulation device 100. For example, the rule application engine 888 can generate instructions for electrical stimulation patterns based on rules generated by the rule generation engine 886 or stored in memory.

[0162] stimulus synchronization In some embodiments, a sudden burst of stimulation (as shown in FIG. 9A ) is applied to the ear. This, in one embodiment, helps increase patient comfort for certain patients where synchronous stimulation can 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 pulses are turned on at full power, there is no build-up period to mask the intensity of the stimulation sensation. Thus, in some embodiments, the rules application engine 886 can be programmed to generate stimulation instructions that are incremental for each stimulation burst.

[0163] For example, the rule application engine 886 can generate a progressive burst pattern as shown in FIG. 9B. The burst pattern can start at a lower stimulation intensity and then gradually increase to a selected intensity. For example, if the selected intensity is set to 3 mA, at the beginning of each pulse, the amplitude can start at an initial intensity, such as 0.4 mA, and change in increments of 0.1 mA to reach the selected amplitude within a time period of 0.5 seconds. In some cases, the rule generation engine 886 can determine the initial intensity, increments, and time period based on the learning algorithm described above.

[0164] In additional cases, the rules application engine 886 can generate a progressive initial burst pattern as shown in FIG. 9C. The initial pulse at the beginning of stimulation can be ramped up. For example, if the selected amplitude is 3 mA, the first phase can be extended so that at the beginning of each pulse, the initial amplitude starts at 0.4 mA and changes by 0.1 mA increments to reach the selected amplitude over a period of 0.5 seconds. In some cases, the second phase may need to be increased in amplitude and / or duration to maintain charge balance throughout the entire phase.

[0165] In some embodiments, the stimulation may increase by 0.05 to 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) over a period of 0.5 to 30 seconds or more (e.g., 0.5 to 2, 2 to 5, 5 to 10, 10 to 15, 15 to 30 seconds, and overlapping ranges therein), or the increase may increase by about 10 to 50%, 50 to 100%, or 2-fold per increment. The difference between the increments may be constant or may vary. For example, the incremental increase or rise may be from 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 (and higher as needed). Alternatively, the gradual increase or ramp-up may start at 0.5 mA and steadily increase by 0.2 mA to reach a set point, such as 2.5 A. The ramp-up may occur each time stimulation is first turned on, or may occur as the user increases stimulation during a treatment session. The ramp-up may be adjusted by the user, or may be automated by the system. In some embodiments, a ramp-up is included. In some embodiments, the gradual increase or ramp-up may also be used for non-burst stimulation (such as tonic stimulation).

[0166] The rules application engine 886 can also generate other progressive stimulation patterns that are variations of the above patterns to improve comfort and reduce the impact of the electrical stimulation on the user.

[0167] In some embodiments, the devices, systems, and methods described above and claimed herein are used to treat depression (including, but not limited to, postpartum depression, depression associated with neurological disorders, major depression, seasonal affective disorder, depressive disorders, etc.). In some embodiments, inflammation, including, but not limited to, inflammatory gastrointestinal disorders and skin disorders, is also treated. Inflammation, in some embodiments, includes neuroinflammation. In one embodiment, Lyme disease and chronic fatigue syndrome are treated (including chronic inflammatory conditions and symptoms). In some embodiments, neurological disorders (such as Parkinson's disease and Alzheimer's disease) and their associated symptoms and manifestations are treated (e.g., depression, tremors, movement disorders, etc.). In some embodiments, rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, osteoarthritis, and psoriasis are treated. Cardiac conditions (such as atrial fibrillation, high blood pressure, stroke, etc.) can also be treated via neuromodulation, as described in some embodiments herein. Epilepsy and other seizure disorders are treated in one embodiment. Headache disorders, such as migraine, are treated in other embodiments.

[0168] In some embodiments, the neuromodulation (e.g., stimulation) devices described herein are placed on the wrist or finger, or elsewhere on the arm, instead of or in addition to the ear. One, two, three, or four neuromodulation devices may be worn. For example, 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 operated separately or together (e.g., synchronized). In some embodiments, a system for applying neuromodulation to a subject includes multiple neuromodulation devices placed on or near different parts of the subject's body. For example, such a system may include a first neuromodulation device (such as any of the auricle devices 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 (e.g., the wrist, a finger, a portion of the arm, etc.).

[0169] In some embodiments, the system can include multiple neuromodulation devices that communicate wirelessly with each other and provide synchronized patterned stimulation. In some embodiments, multiple neuromodulation devices can be electrically connected with multiple electrode pairs to simultaneously stimulate multiple nerves. In one embodiment, the system can include a neuromodulation device on the wrist or other location on the arm to target a nerve (e.g., the median nerve) of the subject, and an ear neuromodulation device (such as any of the auricle devices described herein) to target the vagus nerve. In some embodiments, such a neuromodulation device on the wrist or arm includes one or more electrodes at least partially surrounding the wrist, a skin interface to ensure good electrical contact to the user, an electronics box or housing to house the stimulator, one or more physiological sensors and other associated electronics such as a controller or processor for executing instructions, memory for storing instructions, a user interface that can include a display and buttons, a communications module, a battery that can be rechargeable and, optionally, an induction coil for charging the battery, and / or a band to hold all components together and securely fasten the device 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. Multiple neuromodulation devices can provide synchronous stimulation to multiple nerves. The stimulation can be, for example, burst, offset, or alternating between multiple nerves.

[0170] Vagal modulation is achieved, according to some embodiments, using the devices described herein. In some embodiments, the devices described herein are used to stimulate the autonomic nervous system. In some embodiments, the devices described herein are used to balance the sympathetic / parasympathetic nervous system.

[0171] In some embodiments, a method of treating and / or applying neuromodulation to a user includes receiving electroencephalography (EEG) data about the user and generating parameters for 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 about the user. This may be particularly advantageous for enabling customized stimulation based on specific abnormal neuronal oscillations that may contribute to one or more conditions of the user (such as migraine or other headache conditions). In some embodiments, the EEG data may be recorded using a single-channel, two-channel, four-channel, eight-channel, sixteen-channel, thirty-two-channel system, or a system with more than thirty-two channels, where one or more channels are positioned over a predetermined region of interest.

[0172] In some embodiments, a method for treating a neurological condition using neuromodulation is provided, which may include any number of: positioning a first neuroeffector (e.g., of a first neuromodulation device) on a skin surface adjacent to the median nerve on a user's arm or wrist; positioning a second neuroeffector (e.g., of the first neuromodulation device or the second neuromodulation device) on a skin surface adjacent to a nerve other than the median nerve on the user's arm or wrist; receiving data related to the user, which data is optionally EEG data; generating parameters for a first neuromodulation signal and a second neuromodulation signal, where generating the parameters comprises analyzing the data related to the user; generating, delivering the first neuromodulation signal to the first neuroeffector to modulate the median nerve, and delivering the second neuromodulation signal to the second neuroeffector to modulate a nerve other than the median nerve (e.g., the user's ulnar nerve or vagus nerve), thereby treating the neurological condition.

[0173] In some embodiments, a method for treating migraine headaches using epicutaneous peripheral nerve stimulation can include any number of: positioning a first peripheral nerve effector (e.g., of a first neuromodulation device) on a skin surface adjacent to the median nerve on a user's arm or wrist; positioning a second peripheral nerve effector (e.g., of the first neuromodulation device or the second neuromodulation device) on a skin surface adjacent to a nerve other than the median nerve on the patient's arm or wrist; delivering a first electrical stimulation signal epicutaneously to the first peripheral nerve effector to stimulate the median nerve; and delivering a second electrical stimulation signal epicutaneously to the second peripheral nerve effector to stimulate the nerve other than the median nerve.

[0174] In some embodiments, a neuromodulation device for treating migraine headaches using epicutaneous peripheral nerve stimulation can include any number of: a first peripheral nerve effector configured to be placed on a skin surface adjacent to the median nerve on a user's arm or wrist; a second peripheral nerve effector configured to be placed on a skin surface adjacent to a nerve other than the median nerve on the patient's arm or wrist; and a controller configured to deliver a first electrical stimulation signal epicutaneously to the first peripheral nerve effector to stimulate the median nerve and a second electrical stimulation signal epicutaneously to the second peripheral nerve effector to stimulate a nerve other than the median nerve (such as the vagus nerve).

[0175] Respiratory-gated auricular stimulation has been demonstrated to target brain networks involved in migraine headaches and shows therapeutic promise. In some embodiments, systems and methods for providing neural stimulation of one, two, or more peripheral nerve targets that modulate vagal tone, parasympathetic outflow, vagal brainstem regions, sympathetic outflow, or sympathetically mediated brainstem regions activate stimulation in phase with a portion of respiration, depending on respiratory cycle measurements. In particular, the systems and methods can use a detection device to detect respiratory cycles over time. If there is a predetermined relationship or correlation between the detected activity and a threshold, such as coincidence, rate of change of activity, or within a predetermined range, the stimulation device is instructed to provide stimulation to at least one or more peripheral nerves. Stimulation can be advantageously correlated with a detected respiratory phase, such as exhalation, providing a potentially synergistically increased effect of the stimulation and thus improved therapeutic benefit. Any of the above-mentioned neuromodulation devices (e.g., any of the auricular devices discussed herein) can be utilized for respiratory-gated auricular stimulation. In some embodiments, the neural stimulation devices and methods disclosed herein do not use or rely on any respiratory synchronization. In some embodiments, the neurostimulation devices and methods disclosed herein use or rely on respiratory gating.

[0176] In some embodiments, peripheral nerve stimulation can advantageously have a synergistic effect when combined with medications, including, but not limited to, antidepressants, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and MAO inhibitors. These effects can include enhanced response to treatment, reduced doses of tricyclic antidepressants, selective serotonin reuptake inhibitors, and MAO inhibitors required to achieve efficacy and therefore fewer adverse reactions, and the like. Combination therapy, in some embodiments, can be beneficial for shortening the time it takes to achieve a therapeutic effect (e.g., by at least 10%, 25%, 50%, or more, or overlapping ranges therein), prolonging the therapeutic effect (e.g., by at least 10%, 20%, 40%, or more, or overlapping ranges therein), or improving overall benefit (e.g., a greater reduction in the magnitude or frequency of mood disorder symptoms).

[0177] According to some embodiments, the neurostimulation embodiments described herein act synergistically with pharmacological agents. Given the already sensitive and inflamed digestive systems of many patients with inflammatory bowel disease and other gastrointestinal conditions, this synergistic effect is particularly beneficial because the patient, in one embodiment, requires a lower overall dose of pharmacological agents to achieve efficacy comparable to (or better than) that achieved without neurostimulation. These pharmacological agents may 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 some embodiments.

[0178] According to some embodiments, the neurostimulation embodiments described herein act synergistically with pharmacological agents for rheumatoid arthritis. This synergistic effect is particularly beneficial for rheumatoid arthritis because, in one embodiment, patients require lower overall doses of pharmacological agents to achieve efficacy comparable to (or better than) that achieved without neurostimulation. These pharmacological agents may include, but are not limited to, traditional disease-modifying antirheumatic drugs (DMARDs), biologics and biosimilars, and JAK inhibitors. This results in fewer undesirable side effects in some embodiments.

[0179] In some embodiments, stimulation modulated by one or more measured biological signals can advantageously have a synergistic effect when combined with medications, including medications for mental health disorders, cardiac disorders, pain, and other diseases. The effect can include an enhanced response to treatment, a lower dose of medication required to achieve efficacy and therefore fewer adverse reactions, etc. This can be beneficial in some embodiments to shorten the time it takes to achieve a therapeutic effect (e.g., by at least 10%, 25%, 50% or more, or overlapping ranges therein), or to prolong the therapeutic effect (e.g., by at least 10%, 20%, 40% or more, or overlapping ranges therein), or to improve overall benefit (e.g., greater reductions in pain, blood pressure, heart rate, arrhythmia frequency, etc.).

[0180] In some embodiments, peripheral nerve stimulation can advantageously have a synergistic effect when combined with medications including triptans, ergots, or CGRP inhibitors. The effect can include an enhanced response to treatment, a lower dose of triptans, ergots, or CGRP inhibitors required to achieve efficacy and therefore fewer adverse reactions, etc. Combination therapy, in some embodiments, can be beneficial for shortening the time it takes to achieve a therapeutic effect (e.g., by at least 10%, 25%, 50% or more, or overlapping ranges therein), prolonging the therapeutic effect (e.g., by at least 10%, 20%, 40% or more, or overlapping ranges therein), or improving overall benefit (e.g., a greater reduction in the magnitude or frequency of migraine symptoms).

[0181] Any of the neuromodulation devices discussed herein (e.g., any of the auricular devices discussed herein) can be utilized to modulate (e.g., stimulate) a subject's vagus nerve, either alone or in combination with one or more other nerves of the subject, e.g., via a separate neuromodulation device, including, but not limited to, the median, radial, ulnar, peroneal, saphenous, tibial, and / or other nerves or meridians accessible to the limb.

[0182] In some embodiments, epicutaneous neuromodulation (e.g., median and / or radial nerve stimulation) in the arm and / or wrist can advantageously inhibit sympathetic excitation-related blood pressure elevation and premotor sympathetic firing in the rostral ventrolateral medulla (rVLM). For example, median and / or radial nerve neuromodulation can provide more convergent inputs to cardiovascular premotor sympathetic neurons in the rVLM.

[0183] In some embodiments, vagus nerve stimulation can also modulate the trigeminal nucleus to suppress inflammation. Thus, in some embodiments, the vagus nerve is stimulated to reduce inflammation via the trigeminal pathway. In other embodiments, the trigeminal nerve is directly stimulated instead of or in addition to the vagus nerve. In some embodiments, epicutaneous nerve stimulation projects to the nucleus tractus solitarius (NTS) and spinal trigeminal nucleus (Sp5) regions to modulate the excitability of the trigeminal sensory complex and its connectivity with higher brain structures. The trigeminal sensory nucleus may be involved in neurogenic inflammation during migraine (e.g., characterized by vasodilation). In some embodiments, vagus nerve stimulation modulates the trigeminal sensory pathway to improve migraine pathophysiology and reduce headache frequency and severity. For example, increased activation of the raphe nucleus and locus coeruleus can suppress nociceptive processing in the sensory trigeminal nucleus. Human skin is well innervated by autonomic nerves, and neuromodulation (e.g., stimulation) of nerves or meridian points as disclosed herein can potentially aid in the treatment of migraines and other headache conditions. For example, epicutaneous neural stimulation of peripheral or distal limb afferent nerves, 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 can increase, reduce, or otherwise balance vasodilation and vasoconstriction through neuromodulation (e.g., the vagus nerve, trigeminal nerve, and / or other nerves around the ear). For example, reduced vasodilation is provided in some embodiments to treat or prevent migraines or other conditions exacerbated by vasodilation. In other embodiments, vasoconstriction is reduced, for example, in conditions where dilation is beneficial (e.g., hypertension and painful conditions). In some embodiments, modulation of blood vessels (either dilation or constriction) 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 reduced inflammation treats tinnitus.

[0184] In various embodiments, neuromodulation of one or more nerves of a subject is responsive to physiological parameters or other information related to the subject (e.g., subject movement, position data). Such physiological parameters or other information may 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 ECG and / or ventricular and / or atrial dyssynchrony using electrodes to measure cardiac rhythm abnormalities), skin conductance (e.g., skin conductance response, galvanic skin response), respiratory rate, skin temperature, pupil diameter, and sleep state (e.g., wakefulness, light sleep, deep sleep, REM). Such information can be analyzed using standard statistical analysis, machine learning, deep learning, or big data techniques such as logistic regression or naive Bayes classifiers to assess the subject's activity state, such as sedentary versus active status and stress level, which may serve as a predictor of migraine or headache attacks or other conditions.

[0185] Sympathetic and parasympathetic nervous activity can be measured by several methods, including microneurography (MSNA), catecholamine testing, heart rate, HRV, or galvanic skin response (GSE). HRV can provide a rapid and effective approximation of autonomic nervous activity in the body. HRV can be determined by analyzing the time interval between heartbeats, also known as the RR interval. Heart rate can be accurately captured through recording devices such as chest straps, finger sensors, or neural effectors (e.g., one, two, four, or six stimulating electrodes). The difference between consecutive RR intervals can provide an indication of a person's cardiac health and autonomic nervous activity. Generally speaking, a healthier heart has greater variability between consecutive RR intervals. This beat-to-beat data can also be used to indicate a user's sympathetic and parasympathetic nervous activity levels. Frequency-domain analysis can separate heartbeat frequencies into distinct bands. High-frequency signals (approximately 0.15-0.4 Hz) can almost exclusively reflect parasympathetic activity, while low-frequency signals (approximately 0.04-0.15 Hz) can represent a mixture of sympathetic and parasympathetic activity. Therefore, taking the ratio of high-frequency (HF) signals to low-frequency (LF) signals can provide an approximation of a person's sympathetic tone. In some embodiments, HRV can be analyzed using, for example, time-domain and geometric-domain methods in addition to frequency-domain methods. In some embodiments, increased heart rate variability can indicate increased parasympathetic response and / or decreased sympathetic response. Reduced heart rate variability can indicate decreased parasympathetic response and / or increased sympathetic response. In some embodiments, the system can detect an increase or decrease in HRV of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, 100% or more relative to a baseline value (or target desired HRV value) and configure changes in one, two or more stimulation modality parameters (e.g., frequency, width, phase, timing, amplitude, offset, neural target, etc.) accordingly.For example, in some embodiments, one, two, or more stimulation modalities can be configured for modulation, such as increasing or decreasing stimulation modality parameters for one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, and / or changing or modifying which of the one or more nerves are targeted, and a response to the therapy can be determined by detecting 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 component of HRV, and a change in the ratio between the high-frequency and low-frequency components of HRV. In some embodiments, one, two, or more stimulation modalities can be configured for modulation, such as increasing or decreasing stimulation amplitude for one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, and a response to the therapy can be determined by detecting 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 component of HRV, and a change in the ratio between the high-frequency and low-frequency components of HRV. In some embodiments, one, two, or more stimulation modalities can be configured for modulation, such as increasing or decreasing stimulation frequency for one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, and a response to the therapy can be determined by detecting 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 component of HRV, and a change in the ratio between the high-frequency and low-frequency components of HRV. In some embodiments, one, two, or more stimulation modalities can be configured for modulation, such as increasing or decreasing pulse width for one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, and a response to the therapy can be determined by detecting 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 component of HRV, and a change in the ratio between the high-frequency and low-frequency components of HRV.In some embodiments, one, two, or more stimulation modalities can be configured for modulation, such as changing or modifying which of one or more nerves associated with the sympathetic and / or parasympathetic nervous systems are targeted (e.g., peripheral nerves) based on detected biomarkers (e.g., heart rate, heart rate variability, cardiac rhythm, sympathetic skin activity, electrodermal activity, wrist-measured body temperature, respiratory cycle, electrical brain activity, and / or cytokine levels, etc.), and a response to treatment can be confirmed by detecting 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 component of HRV, and a change in the ratio of the high-frequency to low-frequency components of HRV. In some aspects, the method provides multiple treatment pathways that depend at least in part on the detection of user biomarkers (e.g., heart rate, heart rate variability, cardiac rhythm, sympathetic skin activity, electrodermal activity, wrist-measured body temperature, respiratory cycle, electrical brain activity, cytokine levels, physical activity, oxygen levels, etc.). In some embodiments, biomarkers may include patient demographics, previous medication use, previous device therapy use, and / or sleep cycles. In some embodiments, additional data, such as weather information at the patient's location (e.g., temperature, humidity, barometric pressure, altitude, etc.), may be monitored to influence the stimulation and / or treatment. In one embodiment, a motion sensor may be used to measure physical activity. In one embodiment, a pulse oximeter may be used to measure oxygen levels (e.g., via pulse oximetry). In some embodiments, one or more biomarkers are detected immediately before, during, and / or after the therapeutic stimulation. In another embodiment, biomarkers are detected hours or days before or after the stimulation. For example, bodily fluids may be used to determine elevated biomarkers such as cytokines or other inflammatory compounds, elevated microorganisms, or low / high electrolytes, and stimulation is applied as a treatment to reduce such biomarkers (or raise them if they are below a desired range). Bodily fluids such as blood, urine, saliva, sweat, tears, nasal discharge, etc., may be used to determine biomarkers.These can be measured using sensors separate (e.g., independent) from or in communication with the neuromodulation components described herein. The sensors can measure a condition (such as microbial levels) or indicate symptoms of a condition (such as elevated body temperature due to microbial infection), either or both of which can be treated with the neuromodulation parameters described herein. In some embodiments, sensors are used after treatment to confirm efficacy or alternative therapies (such as drugs, different or additional non-invasive or implantable neurostimulation, etc.).

[0186] In some embodiments, the balance between parasympathetic and sympathetic activity can be assessed using frequency analysis of heart rate variability measured using pulse plethysmography, which in other embodiments uses an LED light source and optical sensors located within the device to measure fluctuations in light levels due to blood flow targeting one of the major blood vessels around the knee or in the arm, neck, or ear. In some embodiments, heart rate can be measured using accelerometer-based sensors, neuroeffectors (such as one, two, four, or six stimulating electrodes), or electrical-based sensors similar to unipolar or multipolar ECG monitors. In some embodiments, the stimulating electrodes themselves are utilized as sensing elements (e.g., to detect electrodermal activity, cardiac activity, or EEG) and can be placed on or near the subject's ear or on or near a different part of the subject's body (such as the wrist, fingers, or part of the arm).

[0187] In some embodiments, stimulation of one, two, or more nerves in the upper and / or lower extremities can be combined with stimulation of the auricular branch of the vagus nerve (ABVN), for example, via the concha (e.g., the navicular or antrum) or tragus, to regulate vagal activity and restore balance to the autonomic nervous system. Some embodiments of the disclosed systems, devices, and methods can stimulate only the ABVN.

[0188] Any of the neuromodulation devices discussed herein (e.g., any of the auricular devices discussed herein) may respond to several episodes of symptoms, including unilateral pulsating headaches, hypersensitivity to light, sound, and odors, nausea, and possibly dysfunction of the autonomic nervous system, cognitive system, emotional system, and motor system. If more episodes occur per day, treatment may be increased by, for example, increasing the stimulation amplitude, duration of stimulation, or number of treatment sessions. The number of symptom episodes can be detected in various ways to control the stimulation applied by the system and / or device(s). In some embodiments, the subject can input symptom-related events, including, but not limited to, unilateral pulsating headaches, hypersensitivity to light, sound, and odors, and nausea events, on a mobile device configured to communicate directly and / or indirectly with the neuromodulation device.

[0189] In some embodiments, neuromodulation devices are 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 wrists) can be operated simultaneously to simultaneously stimulate target nerves. The stimulation parameters of each device can be the same or different. The two devices can communicate wirelessly to synchronize or offset waveforms between the devices. In some embodiments, the two bilateral neuromodulation devices can be operated in alternation, with only one device delivering stimulation at a time. The alternating devices can alternate stimulation hourly, daily, weekly, or monthly, and the frequency of alternation can be changed based on sensor measurements.

[0190] Treatment via acute palliative and / or preventive therapy pathways In some embodiments, a method framework for treating rheumatoid arthritis, atrial fibrillation, or migraine headaches with peripheral nerve stimulation includes multiple therapeutic pathways (e.g., two or more pathways): (a) an acute relief pathway, and / or (b) a preventative therapy pathway. In one embodiment, the therapeutic framework and each therapeutic pathway may be performed by applying peripheral nerve stimulation via a wrist-worn neuromodulation device, an auricular neuromodulation device, or any combination of a wrist-worn device and an auricular device.

[0191] In one embodiment, the first treatment pathway is an acute relief pathway that includes two phases: a detection phase and a treatment delivery phase. In one embodiment, the detection phase is a treatment phase in which the method identifies the onset of rheumatoid arthritis or acute onset of atrial fibrillation or migraine. These acute onsets may be detected by some sensor measuring biomarkers indicative of a condition within the body or may be self-reported by the user. After an acute episode is detected, a treatment delivery phase is initiated through the neuromodulation device 800. In one embodiment, the treatment delivery phase may be initiated by a prompt on the neuromodulation device for the user to initiate treatment delivery, or may be initiated automatically by the processor 808 and controller or stimulation circuitry 804 within the neuromodulation device 800 upon the achievement of a certain sensor threshold. In one embodiment, this may also be determined by machine learning algorithms, evolutionary algorithms, or some other form of artificial intelligence. The measured biomarkers may include any one or more of heart rate, heart rate variability, cardiac rhythm, skin sympathetic nerve activity, electrodermal activity, temperature measured at the wrist or ear, respiratory cycle, brain electrical activity, and / or cytokine levels.

[0192] In one embodiment, the heart rate threshold may be at least as low as 90 beats per minute. In one embodiment, the heart rate variability threshold may be as low as 1. However, these and any thresholds are likely to be patient-specific and will vary. In one embodiment, the electrical stimulation for therapy delivery may be delivered in bursts of pulses. These bursts may range in frequency from 0 to 150 Hz (e.g., 1, 10, 20, 25, 40, 50, 60, 75, 90, 100, 110, 120, 125, 140, 150 Hz and values ​​and ranges therein), and the pulses may range in frequency from 0 to 15 Hz (e.g., 1, 2, 4, 6, 8, 10, 12, 13, 15 Hz and values ​​and ranges therein).

[0193] In one embodiment, as shown in FIG. 10 , the framework includes cardiac measurement tasks, acute palliative therapy, and preventive therapy. In one embodiment, the cardiac measurement tasks involve performing 90-second heart rate and HRV measurement tasks via PPG while the user remains motionless. These heart rate or HRV measurement tasks may span a time period of 0 to 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 values ​​and ranges therein). These tasks are performed when the user is most susceptible to atrial fibrillation episodes (e.g., after waking up in the morning). No strenuous physical activity occurs more than 10 minutes prior to the measurements. A PPG sensor can optionally be integrated into the stimulation device 800, a base station, or an accessory device.

[0194] In one embodiment, acute palliative therapy is activated when the user's heart rate is abnormally high (e.g., above 100 bpm) enough to consider atrial fibrillation probable. The user delivers one or more 15-minute stimulation sessions, alternating with cardiac measurement tasks, until the heart rate normalizes. These stimulation sessions may span a time period of 0 to 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, an amplitude increase (between the perceived amplitude and the maximum tolerated amplitude) is implemented from one session to the next. In some embodiments, a relatively low stimulation amplitude is utilized.

[0195] In one embodiment, preventative therapy is activated when the HRV (LF:HF ratio) is abnormally high (e.g., a ratio of 2 or greater, or a patient-specific measurement), indicating the user may be in pre-atrial fibrillation. The user delivers one or more stimulation sessions, alternating with cardiac measurement tasks, until the heart rate (LF:HF) normalizes. During initial use, an amplitude increase is implemented from one session to the next (between the sensed amplitude and the maximum tolerated amplitude). In some embodiments, a relatively high stimulation amplitude is utilized.

[0196] In one embodiment, the method detects biomarkers associated with rheumatoid arthritis, atrial fibrillation, or migraine, and provides electrical stimulation in response to the detected biomarker levels. In various embodiments, the method incorporates various types of devices and sensors, including one or more of a wrist-worn device, an auricular device, other peripheral nerve stimulation device, an in-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 in-ear electroencephalogram, or other sensor.

[0197] Respiratory-gated auricular vagal afferent nerve stimulation In various embodiments, as shown in FIGS. 11-15C, a neuromodulation device 800 and system includes an auricular 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 pulses of electrical stimulation to an earpiece and electrodes, which then deliver the pulses to the desired nerve. In one embodiment, as shown in FIGS. 11 and 12, the auricular device 100 includes an earbud-like earpiece with two electrodes protruding from the top of the earphone / earpiece boot 165. In one embodiment, the electrodes can stimulate the auricular branch of the vagus nerve. In one embodiment, the earpiece also includes at least one sensor for measuring biomarkers of the user's physiological state and a controller that receives this information to adjust stimulation parameters.

[0198] In one embodiment, the system is configured to deliver stimulation continuously or in pulses with a pulse frequency that can range from 1 to 100 Hz. In one embodiment, the stimulator can have a round "puck-like" form factor and can be attached via a clip to a belt, shirt, or some other article of clothing. In one embodiment, the stimulator can also be integrated into an earpiece, so that the earpiece resembles a hearing aid.

[0199] In one embodiment, an additional stimulation device can be added to the system, as shown in FIG. 13 . The device may be a wrist-worn watch-like device as disclosed in PCT / US2022 / 074376, the entire contents of which are incorporated by reference as part of this disclosure. The watch-like device delivers electrical stimulation to peripheral nerves at the wrist and includes a band with integrated dry electrodes. The electrodes within the band may include a band with two rows of three electrodes, with the center electrode of each row being a charge-balancing electrode and the electrodes on either side of the center electrode being stimulating electrodes. The device delivers bursts of electrical stimulation from a stimulator integrated into the device. The device may include a user interface with an electronic ink display on the surface of the watch-like device. It may also include a base station for charging and storing the device.

[0200] 14A-14B illustrate a neuromodulation device delivering electrical stimulation to the auricular branch of the vagus nerve according to an embodiment of the present disclosure. FIGS. 15A-15C illustrate a neuromodulation device delivering electrical stimulation to the auricular branch of the vagus nerve according to an embodiment of the present disclosure. In one embodiment, various sensors 812 are incorporated into the system to measure various biomarkers. In one embodiment, one such sensor may be a photoplethysmography sensor, and the measured biomarker is heart rate or heart rate variability. Another sensor may be an electrocardiogram (ECG) and biomarker cardiac rhythm. The EKG may be integrated into a watch-like device, a base station, or a patch worn on the user's body. Another sensor may be a sensor for detecting biomarkers of skin sympathetic nerve activity. One of the aforementioned sensors may also potentially detect electrodermal activity or skin temperature. Another potential sensor may be a mechanical sensor integrated into a belt worn around the chest that detects changes in respiratory cycle. Another sensor may be a microphone worn in the ear to detect changes in the user's respiratory cycle. Another sensor may measure temperature within the ear. Another sensor may be an infrared reflected light monitor integrated into the earpiece to detect changes in the user's breathing cycle. Another potential sensor may be an electroencephalogram integrated into the earpiece to measure brain activity. Another potential sensor may measure cytokine levels in the body and be integrated into a stimulation device, skin patch, or belt.

[0201] In one embodiment, the electrical stimulation device may wirelessly communicate with the aforementioned belt respiratory sensor and deliver electrical stimulation via a conduit to an earpiece. In this system, the earpiece may be a silicone boot 165 that rests at the entrance to the ear canal, or a clip that attaches to the helix of the ear and includes a reflective or transmissive photoplethysmography sensor.

[0202] In one embodiment, the system may be used to provide acute treatment to a user suffering from migraines, colitis, irritable bowel disease, rheumatoid arthritis, high blood pressure, episodes of atrial fibrillation, or other cardiac arrhythmias or conditions. It may also be used to prevent future episodes of atrial fibrillation or other cardiac arrhythmias. In one embodiment, the device includes earpieces 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 provide a variety of therapeutic benefits, including treatment of atrial fibrillation or other cardiac arrhythmias, colitis, rheumatoid arthritis, migraines, irritable bowel disease, and high blood pressure. The present invention may be used in conjunction with other neuromodulation devices (e.g., those worn on the wrist) to enhance therapeutic benefits.

[0203] Algorithm for detecting the inspiratory and expiratory phases of breathing In various embodiments, algorithms for determining a person's current respiratory phase and determining when a respiratory phase begins or ends are shown in Figures 16-17. In various embodiments, the algorithms can be used for a variety of applications including, but not limited to, respiratory-gated peripheral nerve stimulation, underwater breathing devices, aviation training, athletic training, sleep apnea, diagnosis of irregular breathing conditions, meditation, and treatment of anxiety conditions.

[0204] In one embodiment, a method for determining a user's respiratory phase involves using a sensor to detect and measure respiration, which produces some quantitative measure of the user's respiratory state. A 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.

[0205] In one embodiment, one such parameter used by the algorithm is the respiration threshold, which is the minimum difference in amplitude between two sample values ​​obtained from the sensor.

[0206] In one embodiment, a second potential type of parameter may be a sample check count, which is the minimum number of samples in a sequence that must be checked to consider whether the user has switched from one respiratory phase to another (e.g., from inspiration to expiration).

[0207] In one embodiment, a third potential type of parameter may be a respiratory gradient threshold, which is a minimum gradient value for assigning a change from one respiratory phase to another (e.g., from inspiration to expiration).

[0208] In one embodiment, a fourth potential parameter may be a lockout length, which is the minimum amount of time the algorithm is paused. The algorithm may also include a genetic evolutionary 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.

[0209] In one embodiment, the respiratory state is determined from the respiratory data via a respiratory threshold. The amplitude distance between samples is a measure for considering changes in state. Optionally, adaptive or steady-state breathing is considered.

[0210] In one embodiment, the respiratory state is determined from the respiratory data via a sample check count, which is the number of samples in a sequence that increase or decrease by a response threshold used to trigger a respiratory state change.

[0211] In one embodiment, the respiratory state is determined from the respiratory data via a respiratory gradient threshold, which is the absolute amplitude change between the first and last samples of the sample check count to trigger a respiratory state change.

[0212] In one embodiment, the respiratory state is determined from the respiratory data via a lockout length, which is the number of samples after a respiratory state change before another respiratory state change can occur.

[0213] A flow chart diagram of one embodiment of this algorithm is shown in Figure 17. In various embodiments, a method for determining a user's respiratory phase includes a sensor for detecting and measuring respiration and generating sample values, and a controller that receives values ​​from the sensor and applies an algorithm using various parameters to determine whether a person is exhaling or inhaling.

[0214] In one embodiment, one of the parameters used by the algorithm is a respiratory threshold, which is the minimum difference in amplitude between two sample values. In one embodiment, one of the parameters used by the algorithm is a sample check count, which is the minimum number of samples in a sequence that must be checked to consider whether the user has switched from one respiratory phase to another. In one embodiment, one of the parameters used by the algorithm is a respiratory slope threshold, which is the minimum slope value required to assign a change from one respiratory phase to another. In one embodiment, one of the parameters used by the algorithm is a lockout length, which is the minimum amount of time the algorithm will be paused. In one embodiment, one respiratory phase relative to another is inspiration versus expiration.

[0215] Further Considerations and Terminology Conditional language used herein, particularly "can," "could," "might," "may," "eg," and the like, is generally intended to convey that certain features, elements, and / or steps are optional, unless otherwise specified or understood otherwise within the context in which it is used. Thus, such conditional language is generally not intended to imply that features, elements, and / or steps are in any way required, or that one or more embodiments necessarily include logic for determining whether these features, elements, and / or steps should be included or always performed, regardless of the presence or absence of other input or prompts. Terms such as "comprising," "including," and "having" are synonymous and are used in an inclusive, open-ended manner and do not exclude additional elements, features, actions, operations, etc. Additionally, the term "or" is used in an inclusive (rather than exclusive) sense; for example, when used to connect a list of elements, the term "or" may refer to one, some, or all of the elements in the list. Furthermore, as used herein, the term "each," in addition to having its ordinary meaning, can refer to any subset of the set of elements to which the term "each" applies.

[0216] Connecting words such as the phrase "at least one of X, Y, and Z," unless otherwise specified, are otherwise understood in the context in which they are generally used to convey that an item, term, etc. can be either X, Y, or Z. Thus, such connecting words are generally not intended to imply that a particular embodiment requires the presence of at least one of X, at least one of Y, and at least one of Z.

[0217] As used herein, terms of degree, such as "approximately," "about," "generally," and "substantially," refer to a value, amount, or characteristic that is close to a stated value, amount, or characteristic that still performs a desired function or achieves a desired result. For example, the terms "approximately," "about," "generally," and "substantially" can refer to an amount that is less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated amount. As another example, in certain embodiments, the terms "approximately parallel" and "substantially parallel" refer to a value, amount, or characteristic that deviates from exact parallelism by no more than 10 degrees, 5 degrees, 3 degrees, or 1 degree. As another example, in certain embodiments, the terms "approximately perpendicular" and "substantially perpendicular" refer to a value, amount, or characteristic that deviates from exact perpendicular by no more than 10 degrees, 5 degrees, 3 degrees, or 1 degree. The terms "approximately," "about," "generally," and "substantially" are inclusive of the number following such term. For example, "about 10 mm" includes support for the value 10 mm.

[0218] While specific embodiments and examples have been described herein, it will be understood by those skilled in the art that many aspects of the systems and devices shown and described in this disclosure can be differently combined and / or modified to form still further embodiments or acceptable examples. All such modifications and variations are intended to be within the scope of the present disclosure. A wide variety of designs and approaches are possible. No feature, structure, or step disclosed herein is essential or essential.

[0219] Any methods disclosed herein do not have to be performed in the order listed. The methods disclosed herein may include specific actions performed by a practitioner. However, they may also include any third-party instruction of those actions, either explicitly or implicitly.

[0220] The methods and tasks described herein can be performed and fully automated by a computer system. The computer system may, in some cases, include multiple separate 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 typically includes a processor (or multiple processors) that executes program instructions or modules stored in memory or other non-transitory computer-readable storage media or devices (e.g., solid-state storage devices, disk drives, etc.). Various functions disclosed herein may be embodied in such program instructions and / or implemented in the computer system's application-specific circuitry (e.g., ASIC or FPGA). When a computer system includes multiple computing devices, these devices may, but need not, be co-located. 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 magnetic disks, to different states. The computer system may also be a cloud-based computing system whose processing resources are shared by multiple different business entities or other users.

[0221] Depending on the embodiment, certain acts, events, or functions of any of the processes or algorithms described herein may be performed in a different order, added, combined, or entirely omitted (e.g., not all acts or events described may be required to practice an algorithm). Furthermore, in certain embodiments, acts or events may not be sequential but may be performed simultaneously, for example, via multithreading, interrupt processing, or multiple processors or processor cores, or on other parallel architectures.

[0222] Various illustrative logic blocks, modules, routines, and algorithm steps that may be described in connection with the disclosure herein may be implemented as electronic hardware (e.g., ASIC or FPGA devices), computer software running on general-purpose computer hardware, or a combination of both. Various illustrative components, blocks, and steps may be described herein generally 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 design constraints imposed on the overall system. The described functionality may be implemented in various ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the present disclosure.

[0223] Furthermore, various illustrative logic blocks and modules that may be described in connection with the disclosure herein may be implemented or performed by machines such as general-purpose processors, digital signal processors (DSPs), application-specific integrated circuits (ASICs), field-programmable gate arrays (FPGAs) or other programmable logic devices, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general-purpose processor device may be a microprocessor, but in alternative examples, the processor device may be a controller, microcontroller, or state machine, combinations thereof, etc. A processor device may include electrical circuitry configured to process computer-executable instructions. A processor device may include an FPGA or other programmable device that performs logical operations without processing computer-executable instructions. A processor device may also be implemented as a combination of computing devices, such as a combination of a DSP and a microprocessor, multiple microprocessors, one or more microprocessors in combination with a DSP core, or any other such configuration. While described herein primarily with respect to digital technology, a processor device may also include primarily analog components. For example, some or all of the rendering techniques described herein may be implemented with analog circuitry or mixed analog-digital circuitry. The computing environment may include any type of computer system, including, but not limited to, a computer system based on a computational engine within a microprocessor, mainframe computer, digital signal processor, portable computing device, device controller, or appliance, to name a few.

[0224] Elements of any method, process, routine, or algorithm described in connection with the disclosure herein may be embodied directly in hardware, in a software module executed by a processor device, or in a combination of the two. A software module may 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 exemplary storage medium may 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 may be integrated into the processor device. The processor device and the storage medium may reside in an ASIC. The ASIC may reside in a user terminal. In the alternative, the processor device and the storage medium may reside as discrete components in a user terminal.

[0225] While the above detailed description has illustrated, described, and pointed out novel features, it will be understood that various omissions, substitutions, and changes in the form and details of the illustrated devices or algorithms may be made without departing from the spirit of the disclosure. As will be understood, certain portions of the description herein may be embodied in a form that does not provide all of the features and advantages described herein, since some features may be used or practiced separately from other features. The scope of the specific embodiments disclosed herein is indicated by the appended claims, rather than the foregoing description. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

1. A neuromodulatory system comprising: an earpiece and an electrical stimulation pulse generator; the electrical stimulation pulse generator is configured to deliver a plurality of electrical stimulation pulses to the earpiece; The earpiece is configured to be placed in a user's ear, the earpiece comprising: a boot placed on the concha; a first electrode protruding from the boot; a second electrode protruding from the boot; 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; Equipped with 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; the first pressure applicator is configured to urge the first electrode in a first direction toward the ear by increasing a level of a first pressure at the first electrode against the ear so as to decrease a first impedance between the first electrode and the ear; the second pressure applicator is configured to urge the second electrode in a second direction toward the ear by increasing a level of second pressure at the second electrode against the ear so as to decrease a second impedance between the second electrode and the ear; Neuroregulatory system.

2. further comprising one or more sensors that measure biomarkers; the biomarker is indicative of a condition of the user; the first electrode and the second electrode are configured to deliver the plurality of electrical stimulation pulses to treat the condition. The neuromodulation system of claim 1 .

3. the boot comprises silicone, the boot is configured to rest at the entrance of the ear canal; The earpiece includes a clip configured to attach to the helix of the ear. The neuromodulation system of claim 1 .

4. The neuromodulation system of claim 1 , wherein the electrical stimulation pulse generator is integrated into the earpiece.

5. A neuromodulatory system comprising: an earpiece in communication with the electrical stimulation pulse generator; The earpiece is configured to be placed in or around an ear, the earpiece comprising: a boot configured to rest in or around the ear; two electrodes protruding from said boot; a pressure applicator having an actuation surface connected to at least one of said two electrodes; Equipped with at least one of the two electrodes delivers electrical stimulation pulses to stimulate the auricular branch of the vagus nerve; the pressure applicator is configured to urge the at least one of the two electrodes in a direction toward the ear by increasing pressure on the at least one of the two electrodes against the ear so as to reduce impedance between the at least one of the two electrodes and the ear; Neuroregulatory system.

6. further comprising one or more sensors that measure biomarkers; the biomarker is indicative of a condition of the user; the at least one of the two electrodes is configured to deliver the electrical stimulation pulses to treat the condition. The neuromodulation system of claim 5 .

7. 7. The neuromodulation system of claim 1, wherein the plurality of electrical stimulation pulses are configured to provide treatment to the user suffering from migraine headaches, colitis, irritable bowel disease, rheumatoid arthritis, high blood pressure, or atrial fibrillation.

8. The neuromodulation system of any one of claims 1 to 6, wherein the electrical stimulation pulse generator comprises a clip configured to be attached to an article of clothing.

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

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

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

12. The neuromodulation system of any one of claims 2 to 4 or 6, wherein the one or more sensors are integrated into any one of the earpiece, skin patch, and belt.

13. The neuromodulation system of any one of claims 2 to 4 or 6, wherein the one or more sensors include a reflection or transmission photoplethysmography sensor.

14. 7. The neuromodulation system of claim 2, wherein the one or more sensors include a microphone worn at the ear to detect changes in the user's breathing cycle.

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

16. 7. The neuromodulation system of claim 2, wherein the one or more sensors include an infrared reflected light monitor integrated into the earpiece for detecting changes in the user's breathing cycle.

17. 10. The neuromodulation system of claim 2, wherein the one or more sensors include an electroencephalogram integrated into the earpiece for measuring brain activity.

18. 7. The neuromodulation system of claim 2, wherein the one or more sensors measure cytokine levels in the body and are integrated into the earpiece, skin patch, or belt.

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

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

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

22. The neuromodulation system of any one of claims 2 to 4 or 6, wherein the biomarker is respiratory cycle or physical activity.

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

24. A neuromodulatory system comprising: an earpiece in communication with the electrical stimulation pulse generator; The earpiece is configured to be placed in or around an ear, the earpiece comprising: a boot configured to rest in or around the ear; two electrodes protruding from said boot; at least one pressure applicator having an actuating surface connected to at least one of said two electrodes; Equipped with at least one of the two electrodes delivers electrical stimulation pulses to stimulate one or more nerves innervating the ear; the at least one pressure applicator is configured to urge the at least one of the two electrodes in a direction toward the ear by increasing pressure on the at least one of the two electrodes against the ear so as to increase electrical conductivity between the at least one of the two electrodes and the ear; Neuroregulatory system.

25. 1. A method of neuromodulation using biomarkers for the treatment of rheumatoid arthritis, atrial fibrillation, or migraine, comprising: positioning a first electrode against the patient's skin adjacent to a first peripheral nerve; positioning a second electrode against the patient's skin adjacent to the first peripheral nerve or a second peripheral nerve; detecting levels of biomarkers associated with rheumatoid arthritis, atrial fibrillation, or migraine; if the sensed level indicates that the user has rheumatoid arthritis, atrial fibrillation, or a migraine, delivering a first electrical stimulus via the first electrode and the second electrode to provide acute relief therapy; if the detected level indicates that the user is experiencing a rheumatoid arthritis, atrial fibrillation, or migraine episode, delivering a second electrical stimulus via the first electrode and the second electrode to provide a symptom-relieving treatment. Including, a value of a stimulation modality parameter of the first electrical stimulus is different from a value of the stimulation modality parameter of the second electrical stimulus; method.

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

27. 26. The method of claim 25, wherein a machine learning algorithm is used to assess when to initiate a treatment delivery phase depending on at least the detected level of the biomarker.

28. 26. The method of claim 25, wherein a predetermined threshold heart rate is greater than 90, 100, 110 or 120 beats per minute, and wherein the acute palliative therapy is administered when the detection level exceeds the predetermined threshold.

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

30. 26. The method of claim 25, wherein the predetermined threshold is determined on a case-by-case basis and is patient-specific.

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

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

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

34. 31. The method of any one of claims 25 to 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. 31. The method of any one of claims 25 to 30, wherein one of the first electrode and the second electrode is configured to be placed on the user's wrist and the other of the first electrode and the second electrode is configured to be worn in or near an ear.

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

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

38. 37. The method of claim 36, wherein the detecting step is performed by patient self-report of symptoms.

39. 37. The method of claim 36, wherein the therapy delivery phase is initiated by instructing a user to initiate delivery of the first electrical stimulus to provide the acute relief therapy or delivery of the second electrical stimulus to provide the therapy.

40. 37. The method of claim 36, wherein the therapy delivery phase is initiated automatically after the detected level indicates that the user is experiencing rheumatoid arthritis, atrial fibrillation, or a migraine, or that the user is at the beginning of experiencing rheumatoid arthritis, atrial fibrillation, or a migraine.

41. 31. The method of any one of claims 25-30, wherein at least one of the first electrical stimulus or the second electrical stimulus is delivered in bursts of pulses.

42. 42. The method of 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. 42. The method of 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. 1. A method of neuromodulation for treating rheumatoid arthritis, atrial fibrillation, or migraine, comprising: positioning a first electrode against the patient's skin adjacent to a first peripheral nerve; positioning a second electrode against the patient's skin adjacent to the first peripheral nerve or a second peripheral nerve; detecting a level of a biomarker associated with rheumatoid arthritis, atrial fibrillation, or migraine, wherein the biomarker is heart rate; if the sensed level indicates that the user has rheumatoid arthritis, atrial fibrillation, or a migraine, delivering electrical stimulation via the first electrode and the second electrode to provide acute relief therapy; A method comprising:

45. 1. A method of neuromodulation for treating rheumatoid arthritis, atrial fibrillation, or migraine, comprising: positioning a first electrode against the patient's skin adjacent to a first peripheral nerve; positioning a second electrode against the patient's skin adjacent to the first peripheral nerve of a second peripheral nerve; detecting a level of a biomarker associated with rheumatoid arthritis, atrial fibrillation, or migraine, wherein the biomarker is heart rate variability; if the detected level indicates that the user is experiencing the onset of rheumatoid arthritis, atrial fibrillation, or a migraine, delivering electrical stimulation via the first electrode and the second electrode to provide symptomatic relief therapy; A method comprising:

46. 46. ​​The method of claim 44 or 45, wherein the electrical stimulation is delivered in bursts of pulses.

47. 47. The method of 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. 47. The method of 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. 47. The method of 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. 47. The method of 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. 1. A method of neuromodulation for the treatment of rheumatoid arthritis, atrial fibrillation, or migraine, comprising: positioning a first electrode against the patient's skin adjacent to a first peripheral nerve; positioning a second electrode against the patient's skin adjacent to the first peripheral nerve or a second peripheral nerve; detecting levels of biomarkers associated with rheumatoid arthritis, atrial fibrillation, or migraine; if the detected level indicates that the user has rheumatoid arthritis, atrial fibrillation, or a migraine, delivering a first electrical stimulus to one or more targeted first nerves via the first electrode and / or the second electrode to provide acute relief therapy; if the detected level indicates that the user is at the beginning of having rheumatoid arthritis, atrial fibrillation, or a migraine, delivering a second electrical stimulus via the first electrode and / or the second electrode to one or more targeted second nerves to provide a symptom-relieving treatment; Including, at least one nerve of the one or more targeted first nerves or 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; method.

52. 52. The method of claim 51 , wherein a value of a stimulation modality parameter of the first electrical stimulus differs from a value of the stimulation modality parameter of the second electrical stimulus.

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

54. A neuromodulatory system comprising: an electrical stimulation pulse generator that delivers electrical stimulation pulses to an earpiece placed inside the ear; two electrodes protruding from the top of the boot that rest on the concha of the ear to stimulate the auricular branch of the vagus nerve; and an electrical stimulation pulse generator comprising a pressure applicator configured to bias at least one of the two electrodes in a direction toward the ear; one or more sensors that measure data from one or more biomarkers of the user's physiological condition; a controller that receives and uses the measurement data to adjust one or more stimulation parameters of the electrical stimulation pulses; A neuromodulation system comprising:

55. 55. The neuromodulation system of claim 54, wherein one of the sensors measures cytokine levels in the body and is integrated into the earpiece, skin patch, or belt.

56. 55. The neuromodulation system of claim 54, wherein the pressure applicator is configured to increase a level of pressure applied by the two electrodes against the ear so as to lower an impedance between the two electrodes and the ear.

57. 55. The neuromodulation system of claim 54, wherein the pressure applicator is a spring-loaded actuated surface.

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

59. 55. The neuromodulation system of claim 54, wherein the electrical stimulation is delivered continuously.

60. 55. The neuromodulation system of claim 54, wherein the electrical stimulation pulse generator includes a circular form factor and is attached to an article of clothing via a clip.

61. 55. The neuromodulation system of claim 54, wherein the electrical stimulation pulse generator is integrated into the earpiece to provide a device that resembles a hearing aid in appearance.

62. 1. A wristwatch-like wrist-worn stimulation device that delivers electrical stimulation to peripheral nerves located on the wrist, comprising: a band including two rows of three electrodes; The center electrode of each row is a stimulating electrode; a band, the electrodes on either side of the central electrode being charge-balancing electrodes; a second electrical stimulation pulse generator worn on the wrist that delivers bursts of electrical stimulation pulses to the electrodes on the band; a user interface including a display on a surface of the watch-like wrist-worn stimulation device; and a base station configured to charge and house the watch-like wrist-worn stimulation device; Equipped with 62. The neuromodulation system of any one of claims 54 to 61, further comprising a wristwatch-like wrist-worn stimulation device.

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

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

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

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

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

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

69. 62. A neuromodulation system according to any one of claims 54 to 61, wherein one of the sensors is a sensor for detecting electrodermal activity.

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

71. 62. The neuromodulation system of any one of claims 54 to 61, wherein one of the sensors is a mechanical sensor integrated into a belt worn around the chest that detects changes in respiratory cycles.

72. 62. The neuromodulation system of any one of claims 54-61, wherein the electrical stimulation pulse generator is in wireless communication with a belt respiratory sensor and delivers electrical stimulation to the earpiece via a conduit.

73. 73. The neuromodulation system of claim 72, wherein the earpiece is a silicone boot that rests at the entrance of the ear canal.

74. 73. The neuromodulation system of claim 72, wherein the earpiece is a clip that attaches to the helix of the ear and includes a reflective or transmissive photoplethysmography sensor.

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

76. 62. A neuromodulation system as described in any one of claims 54 to 61, wherein one of the sensors measures temperature within the ear.

77. 62. The neuromodulation system of any one of claims 54-61, wherein one of the sensors is an infrared reflected light monitor integrated into the earpiece for detecting changes in the user's breathing cycle.

78. 62. A neuromodulation system as described in any one of claims 54 to 61, wherein one of the sensors is an electroencephalogram integrated into the earpiece for measuring brain activity.

79. 62. The neuromodulation system of any one of claims 54-61, wherein the system is used to provide acute treatment to a user suffering from migraine headaches, colitis, irritable bowel disease, rheumatoid arthritis, high blood pressure, an episode of atrial fibrillation, or other cardiac arrhythmia or condition.

80. 62. The neuromodulation system of any one of claims 54 to 61, wherein the system is used to alleviate symptoms of a future episode of atrial fibrillation or other cardiac arrhythmia.

81. 1. A system for determining a respiratory phase of a user, comprising: a sensor for detecting and measuring a quantitative value generally related to the respiratory phase of the user, the quantitative value being one or more of a respiratory threshold, a sample check count, a respiratory slope threshold, and a lockout length; a controller configured to apply an algorithm to the quantified value and determine the respiratory phase of the user based on the application of the algorithm to the quantified value; A system comprising:

82. 82. The system of claim 81, wherein the quantitative value is the respiratory threshold, the respiratory threshold being the smallest difference in amplitude between two sample values.

83. 82. The system of claim 81, wherein the quantitative value is the sample check count, and the sample check count is the minimum number of samples in a column that need to be checked to consider whether the user has switched from one respiratory phase to another.

84. 82. The system of claim 81, wherein the quantified value is the respiratory slope and the respiratory slope threshold is the minimum slope value required to assign a change from one respiratory phase to another.

85. 82. The system of claim 81, wherein the quantitative value is the lockout length, the lockout length being a minimum amount of time the algorithm is paused.

86. 86. The system of any one of claims 81 to 85, wherein the determined respiratory phase is an inspiratory phase or an expiratory phase.

87. 1. A method for reducing the dosage of a drug therapy using neurostimulation and a pharmaceutical agent, comprising: positioning a first electrode against the patient's skin within the ear adjacent to a first peripheral nerve; positioning the second electrode against the patient's skin adjacent to the first peripheral nerve or a second peripheral nerve; delivering electrical stimulation via the first electrode and the second electrode to provide neural stimulation therapy; Including, the neurostimulation therapy synergistically reduces the dose and / or duration of the drug therapy with the pharmaceutical agent; (i) positioning an earpiece inside an ear, the earpiece comprising a first electrode, a second electrode, and a pressure applicator, the pressure applicator 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, the quantitative value being one or more of a respiratory threshold, a sample check count, a respiratory slope threshold, and a lockout length; and a controller configured to apply an algorithm to the quantitative value and determine the respiratory phase of the user based on the application of the algorithm to the quantitative value; (iii) detecting a level of a biomarker associated with rheumatoid arthritis, colitis, atrial fibrillation, or migraine, and if the detected level indicates that the user has rheumatoid arthritis, colitis, atrial fibrillation, or migraine, delivering a first electrical stimulus via the first electrode and the second electrode to provide acute relief therapy; further comprising one or more of: method.

88. 1. A method for predicting a patient's responsiveness to additional treatment, comprising: positioning the first electrode against the patient's skin within the ear adjacent to a first peripheral nerve; positioning the second electrode against the patient's skin adjacent to the first peripheral nerve or a second peripheral nerve; delivering electrical stimulation via the first electrode and the second electrode to provide neural stimulation therapy; detecting the patient's responsiveness to the delivered neurostimulation therapy; determining whether the patient is an appropriate candidate for additional treatment based on the detected responsiveness; Including, the additional treatment is selected from one or more of drug therapy, deep brain stimulation, and thalamotomy; (i) positioning an earpiece inside an ear, the earpiece comprising a first electrode, a second electrode, and a pressure applicator, the pressure applicator 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, the quantitative value being one or more of a respiratory threshold, a sample check count, a respiratory slope threshold, and a lockout length; and a controller configured to apply an algorithm to the quantitative value and determine the respiratory phase of the user based on the application of the algorithm to the quantitative value; (iii) detecting a level of a biomarker associated with rheumatoid arthritis, colitis, atrial fibrillation, or migraine, and if the detected level indicates that the user has rheumatoid arthritis, colitis, atrial fibrillation, or migraine, delivering a first electrical stimulus via the first electrode and the second electrode to provide acute relief therapy; further comprising one or more of: method.

89. 89. The method of any one of claims 87 and 88, wherein the neurostimulation therapy reduces side effects of the medication, the side effects being selected from the group consisting of addiction, tolerance, dependence, gastrointestinal problems, nausea, confusion, dyskinesia, and appetite changes.

90. 89. The method of any one of claims 87 and 88, wherein the medication is for the treatment of tremors, epilepsy, depression, anxiety or headaches.

91. 89. The method of any one of claims 87 and 88, wherein the medication is for the treatment of multiple sclerosis, colitis, Crohn's disease, or functional dyspepsia.

92. 89. The method of any one of claims 87 and 88, wherein the medication is for the treatment of rheumatoid arthritis, psoriatic arthritis, psoriasis, or chronic fatigue syndrome.

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

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

95. 95. The system and method of any one of claims 1 to 94, wherein 1, 2, 3, 4, or 5 additional electrodes are used.

96. Use of any one of the devices described herein for the relief 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 the gastrointestinal problems of Parkinson's disease).

97. Use of any one of the devices described herein for the relief of symptoms and / or treatment 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 one of the devices described herein for the relief of symptoms and / or treatment of cardiac conditions (such as atrial fibrillation, high blood pressure, and stroke).

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

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

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

102. Devices and methods for modulating one or more nerves as described herein.

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