Devices, systems, and methods for closed-loop transcutaneous auricular vagus nerve stimulation paired with a patient trigger for enhanced myelin repair and functional recovery in demyelinating diseases

Abstract

A system for treating a subject including a signaling device, a controller, and a stimulator. The signaling device is in communication with the input of the controller and is configured to send a signal to the controller. The stimulator is in communication with the output of the controller and is configured to stimulate an auricular branch of a vagus nerve in an ear of a subject in response to the controller receiving the signal from the signaling device.

Description

DEVICES, SYSTEMS, AND METHODS FOR CLOSED-LOOP TRANSCUTANEOUS AURICULAR VAGUS NERVE STIMULATION PAIRED WITH A PATIENT TRIGGER FOR ENHANCED MYELIN REPAIR AND FUNCTIONAL RECOVERY INDEMYELINATING DISEASESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 607,327, filed December 7, 2023, and is incorporated by reference in its entirety for all purposes.GOVERNMENT FUNDING

[0002] This invention was made with government support under grant number HR0011-17-2- 0051 awarded by DARPA and under grant number APP -442048 funded by the NIH. The government has certain rights in the invention.FIELD

[0003] Embodiments of the present disclosure relate to devices, systems, and methods for treatment of demyelinating conditions. In certain embodiments, the present disclosure relates to devices, systems, and methods for vagus nerve stimulation that can be paired with a patient trigger in the form of a completed motor task, cognitive task, or physiological signal.BACKGROUND

[0004] Demyelinating diseases are neurological conditions characterized by the progressive degradation of myelin sheaths, the insulating tissue surrounding nerve axons. Exposed axons exhibit diminished conductivity and are susceptible to degradation. Affected individuals exhibit a wide range of motor, sensory, and cognitive impairments that disrupt mobility and physical independence. Multiple sclerosis (MS) is the most prevalent demyelinating disease and is the leading cause of nontraumatic neurological disability in young adults. MS is characterized by central nervous system (CNS) inflammation due to gene-environment interactions and subsequent degradation of myelin and oligodendrocytes, the myelin-producing cells. In 2020, the prevalence of MS was approximately 35.9 individuals per 100,000 (equivalent to approximately2.8 million people), which represents a 30% increase from 2013. In 2019, the total estimated economic burden of MS in the United States was an estimated $85.4 billion, with direct medical expenses accounting for $63.3 billion, or 74%.

[0005] A standard treatment for patients with MS is disease-modifying therapy (DMT), which decreases inflammation to slow disease progression. There is an innate response for myelin regeneration in which oligodendrocyte precursor cells differentiate into myelinating oligodendrocytes; however, myelin recovery is often incomplete. This leaves patients vulnerable to further degeneration of exposed axons and progressive functional deficits. Moreover, the average MS patient spends approximately $35,000 per year on DMTs.

[0006] Accordingly, there is a need for interventions that not only halt demyelination in a subject but also promote axonal preservation and functional recovery. Moreover, there is a need for interventions that reduce the substantial financial burden associated with existing treatments.SUMMARY

[0007] Embodiments of the present disclosure include a system for enhancing myelin repair and functional recovery in demyelinating health conditions in a subject. In accordance with these embodiments, the system can include a signaling device, a controller, and a stimulator. The controller has an input and an output. The signaling device is in communication with the input of the controller and configured to send a signal to the controller. The stimulator is in communication with the output of the controller and configured to stimulate an auricular branch of a vagus nerve in an ear of a subject in response to the controller receiving the signal from the signaling device to enhance myelin repair and functional recovery in the subject.

[0008] Embodiments of the present disclosure also include an earpiece. The earpiece includes a body configured to removably couple to an ear of a subject, a stimulating electrode coupled to the first portion of the body and configured to contact a cymba concha of the ear when the body is coupled to the ear, and a return electrode coupled to the body. The body of the earpiece includes a first portion. The stimulating electrode of the earpiece is in communication with a pulse generator and configured to receive a pulse train from the pulse generator such that the stimulating electrode applies transcutaneous stimulation to an auricular branch of a vagus nerve of the ear.

[0009] Embodiments of the present disclosure further include a computer program stored on one or more tangible, non-transitory, computer-readable storage media having executable instructions for performing the computer program on a computing system. The computer program includes receiving a first signal from a signaling device, the first signal associated with an action of a subject, and, upon receiving the first signal from the signaling device, sending a second signal to a stimulator in communication with the signaling device to actuate according to at least one stimulation parameter for stimulating an auricular branch of a vagus nerve in an ear of the subject.

[0010] Embodiments of the present disclosure still further include a method for reducing the progression of, preventing, and / or reducing demyelination in a subject having a demyelination disease, disorder, or condition. The method includes transcutaneously stimulating the auricular vagus nerve of the subject.

[0011] Embodiments of the present disclosure still further include a method of promoting remyelination through oligodendrocyte recovery in a subject having a central nervous system. The method includes transcutaneously stimulating the auricular vagus nerve of the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 illustrates a controller and an ear with a vagus nerve, in accordance with embodiments of the disclosure.

[0013] FIG. 2 illustrates a block diagram of a system for stimulating the auricular branch of the vagus nerve of a subject, in accordance with embodiments of the disclosure.

[0014] FIG. 3 illustrates a block diagram of an external controller of the system, in accordance with embodiments of the disclosure.

[0015] FIG. 4 illustrates a block diagram of an earpiece of the system, in accordance with embodiments of the disclosure.

[0016] FIG. 5 illustrates a motor control device that includes a pegboard and pegs, in accordance with embodiments of the disclosure.

[0017] FIGS. 6A-6B illustrate a front view and a back view, respectively, of an earpiece, according to one embodiment of the present disclosure.

[0018] FIGS. 7A-7B illustrate a front view and a back view, respectively, of an earpiece, according to one embodiment of the present disclosure.

[0019] FIGS. 8A-8B illustrate a front view and a back view, respectively, of an earpiece, according to one embodiment of the present disclosure.

[0020] FIGS. 9A-9B illustrate a front view and a back view, respectively, of an earpiece, according to one embodiment of the present disclosure.

[0021] FIG. 10 illustrates an example computing system that can implement various systems and methods according to one embodiment of the present disclosure.

[0022] FIG. 11 A illustrates an experimental timeline (in weeks) for control, iVNS, and taVNS groups in a cuprizone mouse model of demyelination according to one embodiment of the present disclosure.

[0023] FIG. 1 IB illustrates the model remyelination (%) vs. days post cuprizone for each of the control, iVNS, and taVNS groups according to one embodiment of the present disclosure.

[0024] FIG. 12A illustrates a timeline (in weeks) to test the effects of VNS on functional recovery after demyelination for retraining, retraining with unpaired VNS, and retraining with paired VNS groups in an acceptable mouse model of demyelination according to one embodiment of the present disclosure.

[0025] FIG. 12B illustrates a stimulation paradigm for paired VNS and unpaired VNS according to one embodiment of the present disclosure.

[0026] FIG. 12C illustrates the success rate (%) vs. retraining sessions for both learning alone mice and paired VNS mice according to one embodiment of the present disclosure.

[0027] FIG. 12D illustrates the mean success rate (%) for learning alone mice compared to paired VNS mice according to one embodiment of the present disclosure.

[0028] FIG. 12E illustrates the success rate (%) vs. retraining sessions for both learning alone mice compared to unpaired VNS mice according to one embodiment of the present disclosure.

[0029] FIG. 12F illustrates the mean success rate (%) for learning alone mice compared to unpaired VNS mice according to one embodiment of the present disclosure.

[0030] FIG. 13A illustrates a timeline (in weeks) of a learning alone group and a paired VNS group retraining a task at 2.5 months after demyelination according to one embodiment of the present disclosure.

[0031] FIG. 13B illustrates myelin pattern similarity (%) in a learning alone group and a paired VNS group according to one embodiment of the present disclosure.

[0032] FIG. 13C illustrates myelin pattern restoration (%) vs. the mean success rate (%) during retraining according to one embodiment of the present disclosure.

[0033] FIG. 13D-13E illustrate success rate (%) vs. retaining days for learning alone mice according to one embodiment of the present disclosure.

[0034] FIGS. 13F-13G illustrate success rate (%) vs. retaining days for paired VNS mice according to one embodiment of the present disclosure.

[0035] FIG. 14 illustrates a controller, an ear, and a front view of an earpiece according to one embodiment of the present disclosure.

[0036] FIG. 15A illustrates an example ECG trace recorded from a single subject during taVNS according to one embodiment of the present disclosure.

[0037] FIG. 15B illustrates heart rates lowered by taVNS according to one embodiment of the present disclosure.

[0038] FIG. 15C illustrates vagally mediated heart rate variability increased by taVNS according to one embodiment of the present disclosure.

[0039] FIGS. 16A-16C illustrate a controller, an ear, and views of an earpiece according to one embodiment of the present disclosure.DETAILED DESCRIPTION

[0040] This application incorporates by reference in its entirety for all purposes U.S. Patent Application Number 17 / 581,307, fded January 21 , 2022, and entitled “Motor learning and vagus nerve stimulation (vns) paired with motor learning to treat demyelinating diseases, conditions and disorders”.

[0041] Embodiments disclosed herein concern systems and methods for treating a subject (e.g., a patient) afflicted with a demyelinating health condition (e.g., multiple sclerosis, MS), demyelination, or other conditions of myelin disorder or injury. In accordance with these embodiments, to treat the patient, transcutaneous auricular vagus nerve stimulation is provided to the patient, paired or followed by a trigger provided by the patient, such as successful execution of a task (e.g., motor task, cognitive task) by the patient, or a biometric (e.g., physiological) signal of the patient. This pairing or combination of events leverages intrinsic adaptability of the nervous system of the patient and promotes systems and mechanisms promoting underlying endogenous myelin repair.

[0042] In certain embodiments, a system disclosed herein can include a controller that receives a signal from a device that detects the patient trigger, such as a behavior (e.g., successful task execution) or biometric signal (e.g., heart rate, brain wave voltage and / or frequency). Upon receiving the signal, the controller activates a stimulating device (hereinafter referred to as a “stimulator”), causing the stimulator to stimulate the auricular vagus nerve of the patient. In accordance with these embodiments, stimulation can be provided in the form of electrical stimulation (e-stim), mechanical vibrations, sound energy (e.g., ultrasound), and thermal energy (e.g., temperature fluctuations), among other forms of stimulation. In certain embodiments, the forms of stimulation can be combined forms of stimulation. Additionally, the system can include an earpiece, optionally, having a stimulator that stimulates the auricular vagus nerve. The earpiece may removably couple to the ear of the patient. In this manner, these therapeutic interventions are non-invasive. Treating the patient with the systems and methods disclosed herein can promote myelin repair and enhance functional recovery in demyelinating diseases.

[0043] In other embodiments, in addition to demyelinating diseases, remyelination therapy to restore neurologic and functional outcomes could benefit various forms of neurologic injury, including those resulting from stroke, traumatic brain injury, spinal cord injury, post-COVID syndrome, and myalgic encephalomyelitis / chronic fatigue syndrome, which involve myelin loss. Furthermore, developmental disorders such as autism and cerebral palsy have been linked to atypical myelination processes. Enhanced myelination could provide a therapeutic approach for various neuropsychiatric conditions, including treatment-resistant depression, post-traumatic stress disorder, schizophrenia, anxiety, and Alzheimer’s disease.

[0044] The devices, systems, and methods herein can be used for reducing the progression of, preventing, and / or reducing demyelination in a subject having a demyelination disease, disorder, or condition. In some embodiments the subject can have at least one of multiple sclerosis (MS), stroke, spinal cord injury, post-COVID syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), autism, cerebral palsy, treatment-resistant depression, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis (ALS), chronic inflammatory demyelinating polyneuropathy (CIDP), Batten disease, acute disseminated encephalomyelitis (ADEM), acute optic neuritis (AON), transverse myelitis, Neuromyelitis optica spectrum disorders (NMO), cranial neuropathies, autonomic neuropathies or other neuropathy causing demyelination, traumatic brain injury (TBI), or side effects of a brain injury, accident or a concussion.

[0045] In some embodiments, the devices, systems, and methods can be used to treat symptoms (or side effects) of a condition. In some embodiments, the subject can have Attention- Deficit / Hyperactivity Disorder (ADHD). In accordance with these embodiments, the devices, systems, and methods disclosed herein can be used to treat side effects of ADHD, such as inattentiveness, hyperactivity, and impulsivity, among others.

[0046] In certain embodiments, systems and methods disclosed herein can provide several advantages over conventional systems. For example, the systems and methods can enhance oligodendrocyte replacement. Additionally, pairing the stimulation with a behavior of the patient can improve functional recovery, restore the original myelin pattern, and / or drive long-term functional improvement.Definitions:

[0047] As used herein, the term “closed-loop” refers to nerve stimulation of a subject (e.g., patient) based on a trigger provided by the subject. The trigger can include the successful execution of a task (e.g., motor task, cognitive task) by the subject, a biometric (e.g., physiological) signal of the subject, or a combination thereof, among others. The term “closed- loop” can include a feedback loop where the response to the nerve stimulation is monitored and subsequent nerve stimulation is adjusted in response.

[0048] As used herein, the term “in communication with” can include a wired connection (e.g., Universal Serial Bus, Ethernet) or a wireless connection (e.g., WiFi, Bluetooth).

[0049] As used herein, the term “signal” can include a control signal. In some embodiments, the signal can be collected, processed, and / or integrated using a computer device. In some embodiments, the signal can be collected as analog, digital, or a combination of both signal modalities.

[0050] With reference to FIG. 1, a system 100 is illustrated, according to one embodiment of the present disclosure. The system 100 can be used to treat a subject 10, by stimulating the auricular branch of the vagus nerve 12 of the subject 10 in response to receiving a signal. In some embodiments, the system 100 is a closed loop. In some embodiments, the system 100 includes a feedback loop. As illustrated in FIG. 1, the subject 10 is a human person. However, the disclosure is not so limited, as the subject can be other types of mammals (e.g., animals). For example, the subject can be a dog, cat, or horse, among others.

[0051] The subject 10 (e.g., human, animal) has an auricular branch of the vagus nerve 12 that terminates in the ear 14 (e.g., auricle 16). The ear 14 includes an auricle 16, which further includes a cymba concha 18, cavum concha 20, and antitragus 22, among other parts of the ear 14. In some embodiments, one or more components of the system 100 (e.g., a stimulating electrode) can be positioned on the cymba concha 18 of the ear 14 and the system 100 can provide stimulation of the cymba concha 18 via e-stim. In some embodiments, one or more components of the system 100 (e.g., a return electrode) can be positioned on the cavum concha 20 of the ear 14 and the system 100 can provide stimulation of the cavum concha 20. In some embodiments, one or more components of the system 100 (e.g., a return electrode) can be positioned on the antitragus 22 of the ear 14 and the system 100 can provide stimulation of the anti tragus 22.

[0052] The system 100 includes a computing device 102 (e.g., a controller, a microcontroller) that has an input and an output. The input of the computing device 102 is in communication with a signaling device (not illustrated in FIG. 1), such as a sensor, which is configured to sense when a patient trigger or task is completed. Upon sensing the patient trigger, the sensor (or a component in communication therewith) can send a signal to the computing device 102 or the computing device 102 can otherwise detect the condition of the sensor. In this manner, the computing device 102 can receive the signal from the signaling device. The output of the computing device 102 is in communication with a stimulator (not illustrated in FIG. 1), such asan electrode, which can be part of an earpiece. In this manner, the computing device 102, in response to receiving the signal from the sensor, can cause the stimulator, which can be placed in the ear of the subject, to stimulate the auricular branch of the vagus nerve 12. In some embodiments, the computing device 102 (as illustrated for example in FIG. 1) can include one or more same or similar components as the computing device 1000 (as illustrated for example in FIG. 10).

[0053] In some embodiments, the system 100 is a closed-loop system. In some embodiments, the stimulation of the auricular branch of the vagus nerve 12 is paired with a patient trigger (or condition, or cue), such as a behavior (e.g., successful task execution) or biometric signal. In other words, the signaling device sends the signal to the computing device 102 (or the computing device 102 detects a change in condition of the signaling device) in response to the behavior of the patient and, in response, the computing device 102 causes the stimulator to stimulate the auricular branch of the vagus nerve 12. That is, in some embodiments, the stimulator does not provide stimulation unless there is a specific action that is triggered by the subject. In some embodiments, the system 100 is provided for independent home use. In some embodiments, the system 100 is provided for use up to an hour per day over the course of rehabilitation. In some embodiments, the system 100 is reusable. In some embodiments, the system 100 is wireless (e.g., wireless earpiece) so as to not hinder performance of the behavioral task by the patient. In some embodiments, the system 100 is wired.

[0054] Turning to FIG. 2-4, a block diagram of a system 200 (or system 200 architecture) is illustrated, according to one embodiment of the present disclosure. The system 200 (as illustrated in FIGS. 2-5, can include one or more same or similar components as the system 100 (as illustrated in FIG. 1). In this manner, the system 200 can be used to treat a subject (as illustrated for example in FIG. 1), by stimulating the auricular branch of the vagus nerve (as illustrated for example in FIG. 1) in response to receiving a signal from a signaling device 208. The system 200 can include an external controller 202, a stimulation control module 204, and / or an earpiece 206. Without departing from the teaching in the present disclosure, the various components of the system 200 can be combined into a different arrangement of components, and the system 200 can include more or less components without limitation.

[0055] In some embodiments, the system 200 is a closed-loop nerve stimulation system where stimulation is provided in response to a signal that is triggered by the subject. In some embodiments, the system 200 includes a feedback loop where outcomes from nerve stimulation, for example, are monitored and used to adjust subsequent inputs into the system 200. Stated differently, the system 200 can receive feedback (e.g., subject response to nerve stimulation) and, according to the feedback, the system 200 can adjust the subsequent inputs (e.g., stimulation parameters). For example, the external controller 202 (e.g., signaling device 208) and / or the stimulation control module 204 (e.g., computing device 212) can receive feedback from the delivery of nerve stimulation. As one non-limiting example, the computing device 212 can send a signal, based on a stimulation parameter 214 being within a predetermined range and / or at a predetermined value (e.g., a specific heart rate of the subject), such that the earpiece 206 causes stimulation. The computing device 212 can receive feedback from the subject in response to the stimulation (e.g., the heartrate of the subject). Based on the feedback (e.g., heart rate), stimulation via the earpiece 206 continues when the stimulation parameter 214 remains within the predetermined range and / or at a predetermined value. Based on the feedback, stimulation via the earpiece 206 is ended (or otherwise ceases) when the stimulation parameter 214 moves outside of the predetermined range and / or away from a predetermined value. That is, when the stimulation parameter 214 moves outside of the predetermined range and / or away from a predetermined value, the system 200 can stop sending the stimulation causing signal and / or the system 200 can send a second signal to stop the stimulation.

[0056] In some embodiments, as illustrated in FIG. 2, the system 200 includes an external controller 202, a stimulation control module 204, and an earpiece 206. As an overview, the external controller 202 is the part of the system 200 associated with sensing a patient trigger and providing a signal associated with the patient trigger. The stimulation control module 204 can include a computing device 212 that receives the signal from the signaling device 208 in response to the completion of the patient trigger. Within the stimulation control module 204, a signal can be sent to the earpiece 206 to provide stimulation according to preset treatment parameters from the stimulation parameters 214. In certain embodiments, each of the stimulation control module 204 and the earpiece 206 include a wireless module 216, 222 for wirelessly communication with each other. Once the earpiece 206 receives the signal to provide stimulation according to the stimulation parameters 214, the stimulator 220 is actuated / activated to providestimulation via its energy delivery modality (e.g., e-stim, percussive vibration, sound energy, thermal energy). In this way, the stimulation of the vagus nerve is tied to a predefined trigger that is designed to facilitate myelin repair and functional recovery.

[0057] In some embodiments, the external controller 202 (e.g., signaling device 208) is in communication with the stimulation control module 204 (e.g., computing device 212). In some embodiments, the stimulation control module 204 (e.g., computing device 212) is in communication with the earpiece 206 (e.g., computing device 218). In other embodiments (not illustrated), the system 200 includes the external controller 202 and the earpiece 206. In some embodiments, the external controller 202 (e.g., signaling device 208) is in communication with the earpiece 206 (e.g., computing device 218).

[0058] The external controller 202 can include a signaling device 208 in communication with the stimulation control module 204 (e.g., computing device 212) and / or in communication with the earpiece 206 (e.g., computing device 218). The signaling device 208 is configured to receive a trigger 210 (e.g., a motor task trigger), which causes the signaling device 208 to send a signal. The trigger 210 can include a patient condition, such as a behavior (e.g., successful task execution) or a biometric signal.

[0059] Turning to FIG. 3, a block diagram of the external controller 202 (or external controller 202 architecture) is illustrated, according to one embodiment of the present disclosure. The external controller 202 includes a sensor 300, the trigger 210, and the signaling device 208. The type of sensor 300 can be any type of sensor applicable to the type of patient trigger. Generally, the sensor 300 will sense / detect the patient trigger 210, and, upon completion of the patient trigger, the signaling device 208 will send a signal to the stimulation control module 204 (illustrated in FIG. 2) indicating that the patient trigger has been completed.

[0060] More particularly, the signaling device 208 is configured to send a signal to the computing device 212 and / or computing device 218 (illustrated in FIG. 2) upon execution of the trigger, such as a task being completed by the patient (e.g., motor task, cognitive task) and / or a biometric condition being met. That is, the external controller 202 is configured to send the signal to the earpiece 206 (illustrated in FIG. 2). As discussed above, in some embodiments, the system 200 includes a feedback loop such that the system 200 can adjust the stimulation (e.g., start stimulation, stop stimulation) in response to the feedback (e.g., stimulation parameter 214being within a predetermined range and / or at a predetermined value, stimulation parameter 214 being outside a predetermined range or away from a predetermined value).

[0061] In some embodiments, the external controller 202 includes a mechanical system for behavioral monitoring. In some embodiments, the external controller 202 includes an electronic interface, such as a computer system or application-based program. In some embodiments, the external controller 202 (as illustrated for example in FIGS. 2-3) can include one or more same or similar components as the computing device 1000 (as illustrated for example in FIG. 10).

[0062] In some embodiments, the signaling device 208 is configured to send the signal to computing device 212 and / or to computing device 218 (illustrated in FIG. 2) upon a change in a state of connection 302. The trigger 210 can include a change in the state of connection 302, which causes the signaling device 208 to send the signal. For example, the signaling device 208 can include an electrical circuit (not shown) that has a state of electrical connection (e.g., open, closed). An open state of electrical connection is defined by an open electrical circuit (also referred to as an open circuit). A closed state of electrical connection is defined by a closed electrical circuit (also referred to as a closed circuit). In the case of a circuit, a separate signaling device 208 may not be needed since the act of opening and closing the circuit can be a sufficient signal to the downstream components to operate accordingly. In other embodiments, the signaling device 208 can be configured to send the signal upon a change in the state of electrical connection (e.g., changing from an open state to a closed state, changing from a closed state to an open state).

[0063] In some embodiments, the electrical circuit is part of a motor control device 500, as illustrated for example in FIG. 5. The change in the state of electrical connection can be accomplished by a defined action by the subject that involves fine motor control. As a nonlimiting example, as illustrated in FIG. 5, the motor control device 500 can include a pegboard 502, which contains one or more holes 504, and one or more pegs 506. As a non-limiting example, the defined action by the subject 10 can include inserting (e.g., via a hand 24 of the subject 10) one or more pegs 506 into one or more predetermined holes 504 of the pegboard 502. The electrical circuit can be closed upon the subject inserting one or more pegs 506 into one or more predefined holes 504. Closing of the electrical circuit can be an example of changing the state of connection 302, in FIG. 3. Alternatively, as a non-limiting example, the motor controldevice 500 can include the pegboard 502 with load cells proximate to the one or more holes 504. As a non-limiting example, the pegboard 502 may include one or more compression button load cells or the like that are coaxial with the holes 504 in the pegboard 502. In this way, when a peg 506 is inserted into one of the holes 504, an electrical signal is detected by the load cell indicating that the peg has been inserted into the hole, measuring a change in mass as the peg is added to the pegboard 502. As such, using load cells is a form of a weight-based control system as opposed to a circuit-based control system. As an additional non-limiting example, the motor control device 500 can include the pegboard 502 with light emitting diodes (LEDs) proximate to the one or more holes 504. As a non-limiting example, the pegboard 502 may include one or more LEDs or the like that are coaxial with the holes 504 in the pegboard 502. In this way, when a peg 506 is inserted into one of the holes 504, a change in light emission is detected by photodiodes or phototransistors, among others, to optically detect peg placement.

[0064] Continuing with FIG. 3, in some embodiments, the patient trigger 210 can be provided by the completion of a task by the patient / subject. In this way, the signaling device 208 is configured to send the signal to computing device 212 and / or to computing device 218 (illustrated in FIG. 2) upon a task completion 304 by the subject. The trigger 210 can include the task completion 304 (also referred to as completion of a task), which causes the signaling device 208 to send the signal. For example, as seen in FIG. 3, the task completion 304 can include a motor task 306 (also referred to as a therapeutic motor task), a cognitive task 308, and / or a memory task 310 (also referred to as a memory function). In some embodiments, as discussed below, the signaling device 208 includes the sensor 300 configured to detect a parameter 312. In some embodiments, the sensor 300 is configured to sense a biomarker 314. In some embodiments, the sensor 300 is configured to sense the completion of a task parameter 316 (e.g., motor task parameter, cognitive task parameter).

[0065] In some embodiments, as seen in FIG. 3, the task completion 304 includes the motor task 306 of the subject. That is, the signaling device 208 sends the signal when the subject completes the motor task 306. The motor task 306 can include at least one task parameter (also referred to as a motor task parameter), which can include a position parameter (e.g., hand, arm, leg, foot, or other body position), a velocity parameter, an acceleration parameter, a task outcome parameter (e.g., peg placement in the 9-hole peg task and / or grooved peg task), an electroencephalogram parameter (e.g., scalp, auricular, intracranial), a magnetoencephalogram parameter, anelectromyogram parameter (e.g., indicating muscle activation, force, or timing, including sequence of muscle activation or muscle forces), a heart rate parameter (e.g., heart rate, heart rate variability), a respiration rate parameter, a blood pressure parameter, or a combination thereof. Each of the motor task parameters can be associated with a specific type of sensor 300. For example, the sensor 300 can be a gyroscope or gyro sensor that is part of a smart phone or a band that is placed on the subjects’ arms and / or legs, and the motor task 306 can be to perform certain body movements with the arms and / or legs. Upon the subject meeting the specific task parameters associated with the arm and / or leg movements that are sensed by the gyro sensor, the task can be competed. For example, the motor task 306 may be, but is not limited to, the pressing of a button, the turning of a knob, the insertion of a key, the opening and / or closing of a latch, or the performing of another fine motor activity (e.g., measuring grip force, such as by squeezing, measuring acceleration of hand and / or arm movements, writing, typing, among others). For these non-limiting examples, a device with one or more sensors to measure the motor task 306 may be used.

[0066] In other embodiments, the motor task 306 can include, as discussed above with respect to FIG. 5, inserting one or more pegs 506 into one or more predetermined holes 504 of the pegboard 502. In some embodiments, the electroencephalogram parameter includes specific frequency band power, coherence, and coupling. In some embodiments, the magnetoencephalogram parameter includes specific frequency band power, coherence, and coupling.

[0067] In some embodiments, the task completion 304 includes the cognitive task 308 of the subject. That is, the signaling device 208 sends the signal when the subject completes the cognitive task 308. The cognitive task 308 can include at least one task parameter (also referred to as a cognitive task parameter), which can include an electroencephalogram parameter (e.g., scalp, auricular, intracranial), a magnetoencephalogram parameter, a pupillometry parameter (e.g., pupil position, pupil diameter), a computer interaction parameter, a heart rate parameter (e.g., heart rate, heart rate variability), a respiration rate parameter, a blood pressure parameter, or a combination thereof. In some embodiments, the electroencephalogram parameter includes specific frequency band power, coherence, and coupling. In some embodiments, the magnetoencephalogram parameter includes specific frequency band power, coherence, and coupling.

[0068] In some embodiments, the task completion 304 includes the memory task 310 (also referred to as a memory function or memory encoding / retrieval / consolidation) of the subject. That is, the signaling device 208 sends the signal when the subject completes the memory task 310. The memory task 310 can include at least one task parameter (also referred to as a memory task parameter), which can include an electroencephalogram parameter (e.g., scalp, auricular, intracranial), a magnetoencephalogram parameter, a polysomnogram parameter, a task completion parameter, a computer interaction parameter, a heart rate parameter (e.g., heart rate, heart rate variability), a respiration rate parameter, a blood pressure parameter, or a combination thereof. In some embodiments, the electroencephalogram parameter includes specific frequency band power, coherence, and coupling. In some embodiments, the magnetoencephalogram parameter includes specific frequency band power, coherence, and coupling.

[0069] In some embodiments, the signaling device 208 is configured to send the signal to computing device 212 and / or to computing device 218 (illustrated in FIG. 2) upon detection of a biomarker 314 (such as a biomarker of global cognitive function and sleep) of subject. The trigger 210 can include detection of the biomarker 314, which causes the signaling device 208 to send the signal. In some embodiments, the biomarker 314 (or biomarker parameter) can include, for example, a heart rate parameter, a heart rate variability parameter, a respiration rate parameter, a blood pressure parameter, or a combination thereof. In some embodiments, the biomarker 314 (or biomarker of global cognitive function and sleep) includes an electroencephalogram parameter (e.g., scalp, auricular, intracranial), a magnetoencephalogram parameter, a polysomnogram parameter, a task completion parameter, a computer interaction parameter, a heart rate parameter (e.g., heart rate, a heart rate variability), a respiration rate parameter, a blood pressure parameter, or a combination thereof. In some embodiments, the electroencephalogram parameter includes specific frequency band power, coherence, and coupling. In some embodiments, the magnetoencephalogram parameter includes specific frequency band power, coherence, and coupling.

[0070] As described with reference to FIG. 3, the external controller 202 can include the sensor 300. The sensor can be configured to detect the parameter 312 such as, for example, the biomarker 314 and / or the task parameter 316. The signaling device 208 can send the signal when the sensor 300 detects a value of the parameter 312 (e.g., predetermined value). In some embodiments, a predetermined value (or threshold value) of the parameter 312 must be met orexceeded for the system 200 to send the signal to the earpiece 206 (e.g., computing device 218, stimulator 220, as illustrated in FIG. 2). In some embodiments, a user (e.g., nurse, doctor, healthcare provider, patient) can input the predetermined value into the system 200. For example, if the predetermined value is a heartrate of greater than 90 beats per minute (which is input by the user), then the system 200 will not send the signal to the earpiece 206 (illustrated in FIG. 2) until the heartrate of the patient exceeds 90 beats per minute.

[0071] In some embodiments, the parameter 312 is the task parameter 316 (e.g., motor task parameter) associated with the subject. That is, the sensor 300 is configured to sense the completion of the task parameter 316 (e.g., completion of the motor task 306) by the subject. Upon completion of the task parameter 316, the signaling device 208 sends the signal. The sensor 300 can include, for example, an accelerometer, a gyroscope, an inertial measurement unit, a proximity sensor, a displacement sensor, an optical sensor, a thermal sensor, a camera, a force plate, a touch screen, LiDAR, one or more electrodes, information derived from a camera- enabled computer tracking system, real-time camera tracking and classification, movement tracking software, a pulse oximeter, a flowmeter, sensor-incorporated rehabilitation equipment, or a combination thereof.

[0072] In some embodiments, the parameter 312 is the task parameter 316 (e.g., cognitive task parameter) associated with the subject. That is, the sensor 300 is configured to sense the completion of the task parameter 316 (e.g., completion of the cognitive task 308) by the subject. Upon completion of the task parameter 316, the signaling device 208 sends the signal. The sensor 300 can include one or more electrodes, a super-conducting quantum interference device, a camera, LiDAR, a microphone, a force plate, a touch screen, a mouse, a keyboard, a button, a pulse oximeter, a flowmeter, or a combination thereof.

[0073] In some embodiments, the parameter 312 is the task parameter 316 (e.g., memory task parameter) associated with the subject. That is, the sensor 300 is configured to sense the completion of the task parameter 316 (e.g., completion of the memory task 310) by the subject. Upon completion of the task parameter 316, the signaling device 208 sends the signal. The sensor 300 can include one or more electrodes, a super-conducting quantum interference device, an accelerometer, a microphone, a touch screen, a mouse, a keyboard, a button, a force plate, a pulse oximeter, a flowmeter, or a combination thereof.

[0074] In some embodiments, the parameter 312 is the biomarker 314 (or biomarker of global cognitive function and sleep) associated with the subject. That is, the sensor 300 is configured to sense the biomarker 314 of the subject. Upon detection of the biomarker 314, the signaling device 208 sends the signal. The sensor 300 can include one or more electrodes, a superconducting quantum interference device, an accelerometer, a camera, LIDAR, a microphone, a force plate, a touch screen, a mouse, a keyboard, a touchpad, a pulse oximeter, a flowmeter, or a combination thereof.

[0075] Returning to FIG. 2, the stimulation control module 204 includes the computing device 212 (e.g., a microcontroller) in communication with the signaling device 208. The computing device 212 is configured to receive the signal from the signaling device 208. In some embodiments, the computing device 212 (as illustrated for example in FIG. 2) can include one or more same or similar components as the computing device 102 (as illustrated for example in FIG. 1). In some embodiments, the computing device 212 (as illustrated for example in FIG. 2) can include one or more same or similar components as the computing device 1000 (as illustrated for example in FIG. 10).

[0076] In some embodiments, the computing device 212 can be configured to receive and / or store one or more stimulation parameters 214. For example, a user (e.g., nurse, doctor, healthcare provider, patient) can input the stimulation parameters 214 (e.g., user-specified stimulation parameters). In some embodiments, the stimulation parameters 214 are adjustable (e.g., by the user). In some embodiments, the stimulation parameters 214 (as illustrated in FIG. 2) for an electrical stimulation can include a frequency, an amplitude, a pulse width, and / or an impedance pertaining to a pulse train. In some embodiments, the stimulation parameter 214 for amplitude can be within the range of 0.0 mA to 5.0 mA. In some embodiments, the stimulation parameter 214 for frequency can be within the range of 1 Hz to 150 Hz. In some embodiments, the stimulation parameter 214 for pulse width can be within the range of 50 ps to 750 ps. In some embodiments, the stimulation parameter 214 for impedance can be within the range of 500 Q to 15,000 Q. In some embodiments, impedance monitoring ensures safe and effective stimulation.

[0077] In some embodiments, the stimulation control module 204 includes the wireless module 216 that is in wireless communication with the wireless module 222 of the earpiece 206. The wireless module 216 is in communication with the computing device 212, such that it can receivethe signal from the computing device 212 and / or the signaling device 208. Then, the wireless module 216 of the stimulation control module 204 may wirelessly send the signal to the wireless module 222 of the earpiece 206. In some embodiments, the stimulation control module 204 includes at least one rechargeable battery to power the stimulation control module 204 components (e.g., computing device 212, wireless module 216). In some embodiments, the computing device 212 may be a personal user device (e.g., smartphone) with an application (e.g., a smartphone app) that is paired wirelessly, such as via Bluetooth, to the wireless module 216. The computing device 212 may also be paired wirelessly, such as via Bluetooth, to a physical task effector (such as the motor control device 500 discussed herein) to measure patient actions and reactions (such as, but not limited to, applied force and / or acceleration). The computing device 212 may utilize computer vision to monitor a physical task and / or an app-based task and measure patient actions and reactions (such as, but not limited to, tracing shapes or letters on a touchscreen).

[0078] Continuing with FIG. 2, the earpiece 206 (e g., wireless earpiece) includes the computing device 218. The computing device 218 of the earpiece 206 can receive the signal from the signaling device 208. Upon receiving the signal, the stimulator 220 can be actuated according to at least one stimulation parameter 214 (e.g., a frequency, an amplitude, a pulse width, and / or impedance). In some embodiments, the computing device 218 of the earpiece 206 is in communication with the computing device 212 of the stimulation control module 204. In some embodiments, the computing device 218 of the earpiece is in communication with the signaling device 208 of the external controller 202. In some embodiments, the computing device 218 (as illustrated for example in FIG. 2 and FIG. 4) can include one or more same or similar components as the computing device 102 (as illustrated for example in FIG. 1). In some embodiments, the computing device 218 (as illustrated for example in FIG. 2 and FIG. 4) can include one or more same or similar components as the computing device 1000 (as illustrated for example in FIG. 10).

[0079] The earpiece 206 includes the stimulator 220 (e.g., pulse generator) configured to stimulate the auricular branch of the vagus nerve of the subject (as illustrated in FIG. 1) in response to receiving a signal from the signaling device 208. The stimulation is provided according to the stimulation parameters 214, which can include the length of time, intensity, and wave form characteristics, among other parameters. In some embodiments, the earpiece 206includes the wireless module 222 that is in wireless communication with the wireless module 216 of the stimulation control module 204. That is, the wireless module 222 can wirelessly receive the signal. The wireless module 222 is in communication with the computing device 218 such that it can send the signal to the computing device 218. In this manner, the earpiece 206 is a wireless earpiece, which does not contain external wiring that could interfere with behavior of the patient required to cause the signaling device 208 to send the signal. In some embodiments, the earpiece 206 includes at least one rechargeable battery to power the earpiece 206 components (e.g., computing device 218, stimulator 220, wireless module 222).

[0080] Turning to FIG. 4, a block diagram of the earpiece 206 (or earpiece 206 architecture) is illustrated, according to one embodiment of the present disclosure. The earpiece 206 provides stimulation via a stimulation modality 400. The stimulation modality 400 may include electrical stimulation 402, mechanical -vibration stimulation 404, sound energy stimulation 406 (e.g., ultrasound), thermal stimulation 408, optical stimulation 410 (e.g., near-infrared, visible light with genetically introduced light-sensitive ion channel), or a combination thereof. Electrical stimulation 402 is discussed in further detail, with respect to FIGS. 6A-9B, below. In some embodiments, the stimulation modality 400 includes electrical stimulation 402 and at least one other stimulation modality 400 (e.g., mechanical -vibration stimulation 404, ultrasound stimulation 406, thermal stimulation 408, optical stimulation 410).

[0081] In some embodiments, upon receiving the signal, the computing device 218 (e.g., microcontroller) of the earpiece 206 generates a stimulation pulse train. The pulse train can include one or more stimulation parameters 214 (e.g., user-specified parameters) for frequency, amplitude, and pulse width. When the stimulation parameters 214 are changed in the stimulation control module 204, they are encoded by the computing device 212 (e.g., microcontroller) and transmitted to the earpiece 206. The computing device 218 of the earpiece 206 receives, decodes, and stores the transmitted parameter settings for subsequent stimulation pulse generation.

[0082] Turning to FIGS. 6A-9B, a first earpiece 600 (FIGS. 6A-6B), a second earpiece 700 (FIGS. 7A-7B), a third earpiece 800 (FIGS. 8A-8B), and a fourth earpiece 900 (FIGS. 9A-9B) are each illustrated in a front view and a back view, respectively, according to embodiments of the present disclosure. Each earpiece 600, 700, 800, 900 can be removably coupled to the ear 14 (i.e., inserted in or around the ear) of the subject 10 (illustrated in FIG. 1) such that eachelectrode (e.g., stimulating electrode 604, 702, 804) reliably contacts a particular part of the ear of the patient. In some embodiments, the patient can removably couple the earpiece 600, 700, 800, 900 to their ear. In some embodiments, a conductive hydrogel or elastomer can be applied to one or more electrodes to create a stable, consistent, and comfortable interface between the electrode and the skin.

[0083] Each earpiece 600, 700, 800, 900 (as illustrated in FIGS. 6A-9B) can include one or more same or similar features as the earpiece 206 (as illustrated in FIG. 2). For example, earpiece 600, 700, 800, 900 can include the computing device 218 (e.g., microcontroller) and / or the wireless module 222 coupled to the body 602, 802 of the earpiece 600, 700, 800, 900. In some embodiments, the computing device 218 and / or the wireless module 222 (illustrated in FIG. 2) are disposed within the body 602, 802 (also referred to as internal electronics). Additionally, each earpiece 600, 700, 800, 900 may include the stimulator 220 (e.g., pulse generator and stimulating electrode). The output of the computing device 218 (e.g., microcontroller) is in communication with the pulse generator 412. The pulse generator 412 (as illustrated for example in FIG. 4) can include one or more same or similar components as the pulse generator 1016 (as illustrated for example in FIG. 10). In some embodiments, the pulse generator 412 is coupled to the earpiece 600, 700, 800, 900. In some embodiments, the pulse generator 412 is disposed within the body 602, 802 of the earpiece 600, 700, 800, 900.

[0084] The pulse generator 412 is in communication with the stimulating electrode 604, 702, 804 (as illustrated in FIGS. 6A-9B). In response to the computing device 218 (e.g., microcontroller) receiving the signal from the signaling device 208 (as illustrated in FIG. 2), the pulse generator 412 provides one or more pulse trains to the stimulating electrode 604, 702, 804 (as illustrated in FIGS. 6A-9B). When the stimulating electrode 604, 702, 804 receives the pulse train, the stimulating electrode 604, 702, 804 applies transcutaneous stimulation to the auricular branch of the vagus nerve 12 of the ear 14 of the subject 10 (illustrated in FIG. 1). In some embodiments, the stimulating electrode 604, 702, 804 applies bilateral or unilateral current using biphasic or monophasic pulse trains, respectively, in the auricle of the ear. In some embodiments, the stimulating electrode 604, 702, 804 includes a large electrode surface area to minimize current density through the tissue such that larger stimulus amplitudes can be applied while maintaining comfort of the patient.

[0085] In some embodiments, the subject can wear one earpiece 600, 700, 800, 900 to stimulate the corresponding auricular branch of the vagus nerve. That is, in some embodiments, the earpiece 600, 700, 800, 900 is removably coupled to the left ear of the subject. In other examples, the earpiece 600, 700, 800, 900 is removably coupled to the right ear of the subject. In other embodiments, the subject can wear two earpieces 600, 700, 800, 900. That is, an earpiece 600, 700, 800, 900 is removably coupled to the left ear of the subject and a separate earpiece 600, 700, 800, 900 is removably coupled to the right ear of the subject.

[0086] Turning to FIGS. 6A-7B a first earpiece 600 (FIGS. 6A-6B) and a second earpiece 700 (FIGS. 7A-7B) are illustrated. FIGS. 6A-6B illustrate a front view and a back view, respectively, of earpiece 600, according to one embodiment of the present disclosure. FIGS. 7A-7B illustrate a front view and a back view, respectively, of earpiece 700, according to one embodiment of the present disclosure.

[0087] Due to having same or similar features, earpiece 600 and earpiece 700 are discussed together unless otherwise noted. For example, earpiece 600, 700 includes a body 602 that is configured to removably couple to the ear of the subject. In the case of the earpiece 600 that provides electrical stimulation, the body 602 can include both a stimulating electrode 604 and a return electrode 606 so the electrical path for the current enters the body via the stimulating electrode 604 and exits the body through the return electrode 606.

[0088] The body 602 includes a first portion 608 (also referred to as the anchor of the earpiece 600, 700). The first portion 608 is configured such that, when the body 602 is removably coupled to the ear of the subject, the first portion 608 is positioned in the cymba concha (e.g., cymba concha 18, as illustrated in FIG. 1). The first portion 608 positioned in the cymba concha both secures the body 602 to the ear and guides the placement of the earpiece 600, 700. The stimulating electrode 604 is coupled to the first portion 608 such that, when the body 602 is removably coupled to the ear of the subject, the stimulating electrode 604 contacts the cymba concha. In some embodiments, the stimulating electrode 604 is located at the tip of the first portion 608.

[0089] The stimulating electrode 604 is in communication with a pulse generator (not illustrated) and configured to receive a pulse train from the pulse generator. When the stimulating electrode 604 receives the pulse train, the stimulating electrode 604 applies transcutaneous stimulation tothe auricular branch of the vagus nerve 12 of the ear 14 of the subject 10 (illustrated in FIG. 1). In some embodiments, the pulse generator is coupled to the earpiece 600, 700. In some embodiments, the pulse generator is disposed within the body 602 of the earpiece 600, 700.

[0090] The body 602 includes a second portion 610 (also referred to as the main body of the earpiece 600, 700) extending from the first portion 608. The return electrode 606 is coupled to the second portion 610 such that, when the body 602 is removably coupled to the ear of the subject, the return electrode 606 contacts the cavum concha (e.g., cavum concha 20, as illustrated in FIG. 1).

[0091] A charging port 612 (e.g., two-pin charge port) extends through the second portion 610 of the body 602 and is in communication with the internal electronics (e.g., rechargeable battery). In this manner, the internal electronics can be charged via the charging port 612 such that the internal electronics (e.g., computing device 218, stimulator 220, wireless module 222) can be powered.

[0092] As illustrated for example in FIG. 7, in some embodiments, the earpiece 700 includes a second stimulating electrode 702. The second stimulating electrode 702 is coupled to the second portion 610 of the body 602. The second stimulating electrode 702 is in communication with a pulse generator (not illustrated) and configured to receive a pulse train from the pulse generator. When the second stimulating electrode 702 receives the pulse train, second stimulating electrode 702 applies transcutaneous stimulation to the auricular branch of the vagus nerve 12 of the ear 14 of the subject 10 (illustrated in FIG. 1).

[0093] Turning to FIGS. 8A-9B a third earpiece 800 (FIGS. 8A-8B) and a fourth earpiece 900 (FIGS. 9A-9B) are illustrated. FIGS. 8A-8B illustrate a front view and a back view, respectively, of earpiece 800, according to one embodiment of the present disclosure. FIGS. 9A-9B illustrate a front view and a back view, respectively, of earpiece 900, according to one embodiment of the present disclosure.

[0094] Due to having same or similar features, earpiece 800 and earpiece 900 are discussed together unless otherwise noted. For example, earpiece 800, 900 includes a body 802 that is configured to removably couple to the ear of the subject. The body 802 includes both a stimulating electrode 804 and a return electrode 806.

[0095] The body 802 includes a first portion 808 (also referred to as the anchor of the earpiece 800, 900). The first portion 808 is configured such that, when the body 802 is removably coupled to the ear of the subject, the first portion 808 is positioned in the cymba concha (e.g., cymba concha 18, as illustrated in FIG. 1). The first portion 808 positioned in the cymba concha both secures the body 802 to the ear and guides the placement of the earpiece 800, 900. The stimulating electrode 804 is coupled to the first portion 808 such that, when the body 802 is removably coupled to the ear of the subject, the stimulating electrode 804 contacts the cymba concha. In some embodiments, the stimulating electrode 804 is located at the tip of the first portion 808.

[0096] The stimulating electrode 804 is in communication with a pulse generator (not illustrated) and configured to receive a pulse train from the pulse generator. When the stimulating electrode 804 receives the pulse train, the stimulating electrode 804 applies transcutaneous stimulation to the auricular branch of the vagus nerve 12 of the ear 14 of the subject 10 (illustrated in FIG. 1). In some embodiments, the pulse generator is coupled to the earpiece 800, 900. In some embodiments, the pulse generator is disposed within the body 802 of the earpiece 800, 900.

[0097] The body 802 includes a second portion 810 (also referred to as the main body of the earpiece 800, 900) extending from the first portion 808. In some embodiments, as illustrated for example in FIGS. 8A-8B, the return electrode 806 is coupled to the second portion 810 such that, when the body 802 is removably coupled to the ear of the subject, the return electrode 806 contacts the antitragus (e.g., antitragus 22, as illustrated in FIG. 1).

[0098] The body includes a third portion 812 (also referred to as the over-ear hook of the earpiece 800, 900) extending from the second portion 810. The third portion 812 is configured to hook over, or otherwise wrap around (at least in part), the auricle of the ear (e.g., auricle 16) of the subject to secure the earpiece 800, 900 to the subject. The third portion 812 extends anteriorly into the cavum concha of the ear (e.g., cavum concha). In some embodiments, as illustrated for example in FIGS. 9A-9B, the return electrode 806 is coupled to the third portion 812 such that, when the body 802 is removably coupled to the ear of the subject, the return electrode 806 contacts the posterior side of the auricle (e.g., auricle 16, as illustrated in FIG. 1).

[0099] A charging port 814 (e g., two-pin charge port) extends through the second portion 810 of the body 802 and is in communication with the internal electronics (e.g., rechargeable battery).In this manner, the internal electronics can be charged via the charging port 814 such that the internal electronics (e.g., computing device 218, stimulator 220, wireless module 222) can be powered.

[0100] In some embodiments, a pair of magnets (not shown) can be used to generate additional force on the contact area of an electrode (e.g., stimulating electrode, return electrode). For example, a first magnet can be positioned on an anterior side of the body 802 and a second magnet can be positioned on a posterior side of the body 802. The magnetic force between the first magnet and the second magnet may cause an increase in applied force to the ear via the stimulating electrode 804 and / or the return electrode 806.

[0101] FIG. 10 illustrates a suitable computing and networking environment 1000 (e.g., computing device 1000), according to some embodiments of the present disclosure, which can be part of or useable with the system described herein. In other words, the computing device 1000 can be used to implement various aspects of the present disclosure described herein. The system 100, 200 (as illustrated for example in FIGS. 1-5) can be used to treat a subject by pairing a behavior of the patient, such as successful execution of a task (e g., motor task, cognitive task) by the patient, or a biometric (e.g., physiological) signal (or otherwise biometric condition) of the patient, with stimulation of the auricular branch of the vagus nerve 12 (illustrated in FIG. 1). In some embodiments, the system 100, 200 (as illustrated for example in FIGS. 1-5) can be operated on the computing device 1000 (as illustrated for example in FIG. 10).

[0102] As illustrated, the computing and networking environment 1000 includes a general purpose computing device 1000, although it is contemplated that the networking environment 1000 can include other computing systems, such as smart phones, server computers, hand-held or laptop devices, tablet devices, multiprocessor systems, microprocessor-based systems, set top boxes, programmable consumer electronic devices, network PCs, minicomputers, mainframe computers, digital signal processors, state machines, logic circuitries, distributed computing environments that include any of the above computing systems or devices, and the like.

[0103] Components of the computing device 1000 can include various hardware components, such as a processing unit 1002, a data storage 1004 (e.g., a system memory), and a system bus 1006 that couples various system components of the computing device 1000 to theprocessing unit 1002. The system bus 1006 can be any of several types of bus structures including a memory bus or memory controller, a peripheral bus, and a local bus using any of a variety of bus architectures. For example, such architectures can include Industry Standard Architecture (ISA) bus, Micro Channel Architecture (MCA) bus, Enhanced ISA (EISA) bus, Video Electronics Standards Association (VESA) local bus, and Peripheral Component Interconnect (PCI) bus also known as Mezzanine bus.[00104J The computing device 1000 may further include a variety of computer-readable media 1008 that includes removable / non-removable media and volatile / nonvolatile media but excludes transitory propagated signals. Computer-readable media 1008 can also include computer storage media and communication media. Computer storage media includes removable / non-removable media and volatile / nonvolatile media implemented in any method or technology for storage of information, such as computer-readable instructions, data structures, program modules or other data, such as RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical disk storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium that can be used to store the desired information / data and which can be accessed by the computing device 1000. Communication media includes computer-readable instructions, data structures, program modules or other data in a modulated data signal such as a carrier wave or other transport mechanism and includes any information delivery media. The term “modulated data signal” means a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. For example, communication media can include wired media such as a wired network or direct-wired connection and wireless media such as acoustic, RF, infrared, and / or other wireless media, or some combination thereof. Computer- readable media can be embodied as a computer program product, such as software stored on computer storage media.

[0105] The data storage 1004 (e.g., system memory) includes computer storage media in the form of volatile / nonvolatile memory such as read only memory (ROM) and random access memory (RAM). A basic input / output system (BIOS), containing the basic routines that help to transfer information between elements within the computing device 1000 (e.g., during start-up) is typically stored in ROM. RAM typically contains data and / or program modules that are immediately accessible to and / or presently being operated on by processing unit 1002. Forexample, in one embodiment, data storage 1004 holds an operating system, application programs, and other program modules and program data.

[0106] Data storage 1004 can also include other removable / non-removable, volatile / nonvolatile computer storage media. For example, data storage 1004 can be: a hard disk drive that reads from or writes to non-removable, nonvolatile magnetic media; a magnetic disk drive that reads from or writes to a removable, nonvolatile magnetic disk; and / or an optical disk drive that reads from or writes to a removable, nonvolatile optical disk such as a CD-ROM or other optical media. Other removable / non-removable, volatile / nonvolatile computer storage media can include magnetic tape cassettes, flash memory cards, digital versatile disks, digital video tape, solid state RAM, solid state ROM, and the like. The drives and their associated computer storage media, described above and illustrated in FIG. 10, provide storage of computer-readable instructions, data structures, program modules, and other data for the computing device 1000.

[0107] A user can enter commands and information through a user interface 1010 or other input devices such as a tablet, electronic digitizer, a microphone, keyboard, and / or pointing device, commonly referred to as mouse, trackball, or touch pad. Other input devices can include a joystick, game pad, satellite dish, scanner, or the like. Additionally, voice inputs, gesture inputs (e.g., via hands or fingers), or other natural user interfaces can also be used with the appropriate input devices, such as a microphone, camera, tablet, touch pad, glove, or other sensor. These and other input devices are often connected to the processing unit 1002 through a user interface 1010 that is coupled to the system bus 1006 but can be connected by other interface and bus structures, such as a parallel port, game port, or a universal serial bus (USB).

[0108] The computer system 1000 can include one or more ports, such as an input / output (I / O) port 1012. The I / O port 1012 can be connected to an I / O device, or other device, by which information is input to or output from the computing system 1000. Such I / O devices can include, without limitation, one or more input devices, output devices, and / or environment transducer devices. In some embodiments, the I / O port 1012 is in communication with a pulse generator 1016.

[0109] The computing device 1000 can operate in a networked or cloud-computing environment using a communication module 1014 (e.g., logical connections of a networkinterface or adapter) communicatively coupled to one or more remote devices, such as a remote computer. The remote computer can be a personal computer, a server, a router, a network PC, a peer device, or other common network nodes, and typically includes many or all of the elements described above relative to the computing device 1000. The logical connections depicted in FIG. 10 include one or more local area networks (LAN) and one or more wide area networks (WAN) but may also include other networks. Such networking environments are commonplace in offices, enterprise- wide computer networks, intranets, and the Internet.

[0110] When used in a networked or cloud-computing environment, the computing device 1000 can be connected to a public and / or private network through the communication module 1014. In such embodiments, a modem or other means for establishing communications over the network is connected to the system bus 1006 via the communication module 1014 or other appropriate mechanism. A wireless networking component including an interface and antenna can be coupled through a suitable device such as an access point or peer computer to a network. In a networked environment, program modules depicted relative to the computing device 1000, or portions thereof, can be stored in the remote memory storage device.EXAMPLES

[0111] The materials, methods, and embodiments described herein are further defined in the following Examples. Certain embodiments are defined in the Examples herein. It should be understood that these Examples, while indicating certain embodiments, are given by way of illustration only. From the disclosure herein and these Examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.Example 1 taVNS Enhanced Oligodendrocyte Replacement

[0112] In a cuprizone mouse model of demyelination, transcutaneous auricular vagus nerve stimulation (taVNS) was performed comparably to invasive VNS (iVNS) in its ability to promote remyelination through oligodendrocyte recovery, as illustrated in FIGS. 11 A-l IB. Vagus nerve stimulation (VNS) can have immunomodulatory and / or neuroplastic effects. Insome embodiments, VNS can be used to treat demyelinating diseases. For example, stimulation of the left cervical vagus nerve can induce the production of new oligodendrocytes and preserve surviving oligodendrocytes. In some embodiments, taVNS activates the auricular branch of the vagus nerve (ABVN) with electrodes placed on the surface of the cymba concha in the ear.

[0113] FIG. 11 A illustrates an experimental timeline (in weeks) for control, iVNS, and taVNS groups in the cuprizone mouse model of demyelination and FIG. 1 IB illustrates the model remyelination (%) vs. days post cuprizone for each of the control, iVNS, and taVNS groups. The asymptotic remyelination was significantly improved in both iVNS and taVNS groups compared to control mice and taVNS provided comparable effects on remyelination as compared to iVNS, as illustrated in FIG. 1 IB (one-way ANOVA: p-value<0.001 ; control vs. iVNS: p-value<0.001, control vs. taVNS: p-value=0.003, and iVNS vs. taVNS: p-value=0.16). That is, taVNS enhanced oligodendrocyte replacement. With reference to FIGS. 11 A-l IB, *p- value<0.05, **p-value<0.01, ***p-value<0.001, and n.s.=not significant.Example 2Paired VNS Improved Functional Recovery

[0114] In a cuprizone mouse model of demyelination, the effects of paired VNS (closed- loop) and unpaired VNS (open-loop) were investigated while mice performed a skilled reach task, as illustrated in FIGS. 12A-12F. Paired stimulation paradigms were explored to maximize the therapeutic effects of VNS on motor function by stimulating with high temporal resolution relative to circuit engagement.

[0115] FIG. 12A illustrates the timeline (in experiment weeks) to test the effects of VNS on functional recovery after demyelination for retraining, retraining with unpaired VNS, and retraining with paired VNS groups in a cuprizone mouse model of demyelination. FIG. 12B illustrates the stimulation paradigm for paired VNS and unpaired VNS.

[0116] FIG. 12C illustrates the success rate (%) vs. retraining sessions for both learning alone mice and paired VNS mice. During retraining, paired VNS mice performed significantly better compared to learning alone mice, as illustrated in FIG. 12C (REML; F(l)=5.89, p- value=0.036). FIG. 12D illustrates the mean success rate (%) for both learning alone mice and paired VNS mice. The mean success rate of paired VNS mice was significantly higher than thatof learning alone mice, as illustrated in FIG. 12D (Student’s t-test; t(10)=2.43, p-value=0.036). FIG. 12E illustrates the success rate (%) vs. retraining sessions for both learning alone mice and unpaired VNS mice. Unpaired VNS did not improve motor performance during the retraining phase, as illustrated in FIG. 12E (REML; F(l)=0.01, p-value>0.9). FIG. 12F illustrates the mean success rate (%) for both learning alone mice and unpaired VNS mice. The mean success rate during retraining is similar between learning alone and unpaired VNS mice, as illustrated in FIG. 12F (Student’s t-test; t(8)=0.09, p-value>0.9). With reference to FIGS. 12A-12F, *p-value<0.05, **p-value<0.01, ***p-value<0.001, n.s.=not significant, and error bars represent the mean ± s.e.m.

[0117] While unpaired VNS led to no significant difference in success rate from the group receiving no stimulation (as illustrated in FIGS. 12E-12F), the paired VNS group performed the reaching task significantly better (as illustrated in FIGS. 12C-12D). That is, paired VNS improved functional recovery. It should be noted that the experiment was conducted using iVNS, as opposed to taVNS, due to difficulties associated with reliably stimulating the ABVN in awake mice.Example 3Paired VNS Restored the Original Myelin Pattern and Drove Long-Term Functional Improvement

[0118] In a cuprizone mouse model of demyelination, the myelin patterns for learning alone and paired VNS groups were investigated as a possible mechanism driving enhanced performance, as illustrated in FIGS. 13A-13G.

[0119] FIG. 13A illustrates a timeline (in experiment weeks) of both the learning alone group and the paired VNS group retraining the forelimb reach task at 2.5 months after demyelination. FIG. 13B illustrates the myelin pattern similarity (%) of both the learning alone group and the paired VNS group. Paired VNS increased myelin pattern similarity after demyelination, as illustrated in FIG. 13B (Student’s t-test; t(9)=2.41, p-value=0.039). FIG. 13C illustrates the myelin pattern restoration (%) vs. the mean success % during retraining.Behavioral performance during the retraining phase was strongly correlated with myelin pattern replacement, as illustrated in FIG. 13C (standard least squares regression, shading represents 95% CI).

[0120] FIG. 13D-13E illustrate the success rate (%) vs. retraining days for the learning alone mice. During retraining, learning alone mice did not show any behavioral improvement, as illustrated in FIG. 13D (REML; F(6)=1.98, p-value=0.1). Additionally, a similar level of motor performance between days 1 and 7 during retraining was exhibited for learning alone mice, as illustrated in FIG. 13E (Paired t-test; t(5)=0.87, p-value>0.4).

[0121] FIGS. 13F-13G illustrate the success rate (%) vs. retraining days for the paired VNS mice. Paired VNS mice were able to continue improving their performance during the retraining phase, as illustrated in FIG. 13F (REML; F(6)=3.35, p-value=0.009). Additionally, paired VNS mice showed a significant improvement in success rate during the retraining phase, as illustrated in FIG. 13G (Paired t-test; t(7)=3.61 , p-value=0.009). With reference to FIGS. 13A- 13G, *p-value<0.05, **p-value<0.01, ***p-value<0.001, n.s.=not significant, and error bars represent the mean ± s.e.m.

[0122] Mice receiving paired VNS exhibited a myelin pattern more similar to their myelin pattern before demyelination when compared to learning alone (as illustrated in FIG. 13B), suggesting that VNS drives myelin replacement at the location previously myelinated on the axon, restoring the original myelin pattern. There was a strong correlation between myelin pattern restoration and long-term motor performance (as illustrated in FIG. 13C). While learning alone mice performed similarly across retraining sessions (as illustrated in FIGS. 13D-13E), the paired VNS group showed persisting behavioral improvement (as illustrated in FIGS. 13F-13G). That is, paired VNS restored the original myelin pattern and drove long-term functional improvement.

[0123] With reference to FIG. 14, the system 100 is illustrated, according to another embodiment of the present disclosure. The system 100 can be used to treat the subject 10, by stimulating the auricular branch of the vagus nerve (not illustrated) of the subject 10 in response to receiving a signal. As illustrated in FIG. 14, the subject 10 is a human person. However, the disclosure is not so limited, as the subject can be other types of mammals (e.g., animals). For example, the subject can be a dog, cat, or horse, among others.

[0124] The subject 10 (e.g., human, animal) has an auricular branch of the vagus nerve that terminates in the ear 14 (e.g., auricle 16). The ear 14 includes the auricle 16, which furtherincludes the cymba concha 18, the cavum concha 20, and the antitragus 22, among other parts of the ear 14.

[0125] FIG. 14 illustrates an earpiece 1400, according to one embodiment of the present disclosure. The earpiece 1400 includes an anode 1402 and a cathode 1404. The anode 1402 and / or the cathode 1404 may be an adhesive electrode (e.g., a sticky electrode). The earpiece 1400 is configured such that, when it is removably coupled to the ear 14 of the subject 10, the anode 1402 is positioned in the cymba concha 18 and the cathode 1404 is positioned in the cavum concha 20 to cover the auricular branch of the vagus nerve. In certain embodiments, the earpiece 1440 may be configured such that the anode 1402 is positioned in the cavum concha 20 and the cathode 1404 is positioned in the cymba concha 18. In both embodiments, the anode 1402 and the cathode 1404 are in communication with a pulse generator (not illustrated) and are configured to receive a pulse train from the pulse generator. When the anode 1402 and / or the cathode 1404 receives the pulse train, the earpiece 1400 applies transcutaneous stimulation to the auricular branch of the vagus nerve of the ear 14 of the subject 10. In some embodiments, the pulse generator is coupled to the earpiece 1400. In some embodiments, the pulse generator is disposed within the body of the earpiece 1400.

[0126] The earpiece 1400 is similar to the earpiece 206 illustrated in FIG. 2, in that the earpiece 1400 includes the computing device 218, the stimulator 220, and the wireless module 222. The earpiece 1400 may include a charging port (not illustrated) in communication with the internal electronics of the earpiece 1400 (e.g., rechargeable battery). In this manner, the internal electronics can be charged via the charging port such that the internal electronics (e.g., computing device 218, stimulator 220, wireless module 222) can be powered.EXAMPLES

[0127] The materials, methods, and embodiments described herein are further defined in the following Examples. Certain embodiments are defined in the Examples herein. It should be understood that these Examples, while indicating certain embodiments, are given by way of illustration only. From the disclosure herein and these Examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.Example 4 taVNS Vagally Mediated Autonomic Activity

[0128] FIG. 15A illustrates an example ECG trace recorded from a single subject during taVNS with an anode placed in the cymba concha and a cathode placed in the cavum concha. The taVNS (60s train with 200ps pulse width at 30 Hz and current intensity at the perceptual threshold) with trials (n=10) of 60s ON-120s OFF was accompanied by changes in vagally mediated autonomic activity.

[0129] FIG. 15B illustrates heart rates (HR) lowered by taVNS across N=3 subjects compared to sham stimulation of the scapha. FIG. 15C illustrates vagally mediated heart rate variability increased by taVNS, observed as an increase in the root-mean-square of successive differences (RMSSD) of heartbeat intervals obtained from an ECG recording (p-value<0.01).

[0130] With reference to FIGS. 16A-16C, the system 100 is illustrated, according to another embodiment of the present disclosure. The system 100 can be used to treat the subject 10, by stimulating the auricular branch of the vagus nerve (not illustrated) of the subject 10 in response to receiving a signal. As illustrated in FIGS. 16B-16C, the subject 10 is a human person. However, the disclosure is not so limited, as the subject can be other types of mammals (e.g., animals). For example, the subject can be a dog, cat, or horse, among others.

[0131] The subject 10 (e.g., human, animal) has an auricular branch of the vagus nerve that terminates in the ear 14 (e.g., auricle 16). The ear 14 includes the auricle 16, which further includes the cymba concha 18, the cavum concha 20, and the antitragus 22, among other parts of the ear 14.

[0132] FIG. 16A illustrates an earpiece 1600, according to one embodiment of the present disclosure. The earpiece 1600 is shaped and sized to have a pinch mechanism for simplified self-application, such as for individuals with fine motor deficits. The earpiece 1600 may be fabricated from an elastic material, such that the earpiece 1600 deforms when force is applied by fingers of a user (such as the subject 10) to facilitate insertion into the ear 14 (illustrated in FIG. 16B). Once placed in the ear 14, the earpiece 1600 would attempt to return to its resting shape, remaining partially deformed upon contact with the cymba concha 18 and theantitragus 22 (as illustrated in FIG. 16C), to facilitate a secure fit and reliable skin-electrode contact for effective stimulation.

[0133] The earpiece 1600 includes a stimulating electrode 1602, a return electrode 1604, and a pinch piece 1606 to which a pinch mechanism is applied. The earpiece 1600 is configured such that, when it is removably coupled to the ear 14 of the subject 10, the stimulating electrode 1602 is positioned in the cymba concha 18 and the return electrode 1604 is positioned in the cavum concha 20 to cover the auricular branch of the vagus nerve. The stimulating electrode 1602 is in communication with a pulse generator (not illustrated) and is configured to receive a pulse train from the pulse generator to apply transcutaneous stimulation to the auricular branch of the vagus nerve of the ear 14 of the subject 10. In some embodiments, the pulse generator is coupled to the earpiece 1600. In some embodiments, the pulse generator is disposed within the body of the earpiece 1600.

[0134] The earpiece 1600 is similar to the earpiece 206 illustrated in FIG. 2, in that the earpiece 1600 includes the computing device 218, the stimulator 220, and the wireless module 222. The earpiece 1600 may include a charging port (not illustrated) in communication with the internal electronics of the earpiece 1600 (e.g., rechargeable battery). In this manner, the internal electronics can be charged via the charging port such that the internal electronics (e.g., computing device 218, stimulator 220, wireless module 222) can be powered.

[0135] FIG. 16A illustrates a front and back view of the earpiece 1600 in its resting shape. FIG. 16B illustrates the earpiece 1600 under deformation, with force applied to the pinch piece 1606 by fingers of a user. FIG. 16C illustrates the earpiece 1600 positioned in the ear 14 of the user, with arrows indicating the forces exerted on the ear 14 by the material of the earpiece 1600 to maintain secure placement and optimal electrode contact. The pinch mechanism as described with reference to FIGS. 16A-16C may be applied to any earpiece design described herein.

[0136] The foregoing merely illustrates the principles of the invention. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein. It will thus be appreciated that those skilled in the art will be able to devise numerous systems, arrangements, and methods which, although not explicitly shown or described herein, embody the principles of the invention and are thus within the spiritand scope of the present invention. From the above description and drawings, it will be understood by those of ordinary skill in the art that the particular embodiments shown and described are for purposes of illustrations only and are not intended to limit the scope of the present invention. References to details of particular embodiments are not intended to limit the scope of the invention.

Claims

CLAIMSWhat is claimed is:

1. A system for treating a subject, the system comprising: a controller having an input and an output; a signaling device in communication with the input of the controller and configured to send a signal to the controller; and a stimulator in communication with the output of the controller and configured to stimulate an auricular branch of a vagus nerve in an ear of the subject in response to the controller receiving the signal from the signaling device.

2. The system of claim 1, wherein the signaling device includes an electrical circuit having a state of electrical connection, the state of electrical connection including an open state and a closed state, wherein a change in the state of electrical connection causes the signaling device to send the signal to the controller.

3. The system of claim 2, wherein the electrical circuit is part of a motor control device, wherein a change in the state of electrical connection is accomplished by a defined action of the subject involving fine motor control.

4. The system of claim 3, wherein the motor control device includes a pegboard, and the defined action includes inserting a peg into a hole in the pegboard.

5. The system of claim 1, wherein the signaling device includes a load cell configured to send the signal to the controller, the signal including a value corresponding to a force measured by the load cell.

6. The system of claim 5, wherein the load cell is part of a motor control device, wherein sending of the signal to the controller is accomplished by a defined action of the subject involving fine motor control.

7. The system of claim 6, wherein the motor control device includes a pegboard, and the defined action includes inserting a peg into a hole in the pegboard.

8. The system of claim 1, wherein the signaling device is configured to send the signal to the controller upon a task being completed by the subject, wherein the task includes at least one of a motor task of the subject, a cognitive task of the subject, or a memory function of the subject.

9. The system of claim 1, wherein the signaling device includes a sensor configured to detect a parameter, wherein the signaling device sends the signal to the controller when the sensor detects a value of the parameter.

10. The system of claim 9, wherein the sensor is configured to sense one or more biomarkers of the subject.

11. The system of claim 10, wherein the sensor is configured to sense at least one of heart rate, heart rate variability, respiration rate, or blood pressure.

12. The system according to any one of claims 1-11, further comprising an earpiece, wherein the stimulator comprises one or more stimulating electrodes coupled to the earpiece, the earpiece configured to be supported in or around the ear of the subject, wherein, when the earpiece is supported in or around the ear, a first stimulating electrode of the one or more stimulating electrodes contacts a cymba concha of the ear of the subject.

13. The system of claim 12, wherein the one or more stimulating electrodes comprises a second stimulating electrode.

14. The system of claim 13, wherein the second stimulating electrode contacts an antitragus of the ear of the subject.

15. The system of claim 12, wherein the stimulator further comprises a return electrode coupled to the earpiece.

16. The system of claim 12, wherein the earpiece is an around-the-ear earpiece comprising a hook that extends anteriorly into a cavum concha of the ear of the subject.

17. The system of claim 16, wherein the stimulator further comprises a return electrode coupled to the hook of the earpiece is positioned such that it contacts a posterior side of an auricle of the ear.

18. The system according to any one of claims 1-11, wherein the stimulator is configured to stimulate via a stimulation modality, wherein the stimulation modality comprises at least one of electrical stimulation, mechanical-vibration stimulation, ultrasound stimulation, thermal stimulation, or optical stimulation.

19. The system according to any one of claims 1-11, wherein the signaling device is configured to send the signal to the controller upon a motor task being completed by the subject, the motor task including at least one motor task parameter; wherein the at least one motor task parameter comprises at least one of a position parameter, a velocity parameter, an acceleration parameter, a task outcome parameter, an electroencephalogram parameter, a magnetoencephalogram parameter, an electromyogram parameter, a heart rate parameter, a respiration rate parameter, or a blood pressure parameter; and wherein the signaling device comprises a sensor, wherein the sensor is configured to sense the completion of the at least one motor task parameter.

20. The system of claim 19, wherein the sensor comprises at least one of an accelerometer, a gyroscope, an inertial measurement unit, a proximity sensor, a displacement sensor, an optical sensor, a thermal sensor, a camera, a force plate, a touch screen, LiDAR, one or more electrodes, information derived from camera-enabled computer tracking system, real-time camera tracking and classification, movement tracking software, a pulse oximeter, a flowmeter, or sensorincorporated rehabilitation equipment.21 . The system according to any one of claims 1 -1 1, wherein the signaling device is configured to send the signal to the controller upon a cognitive task being completed by the subject, the cognitive task including at least one cognitive task parameter; wherein the at least one cognitive task parameter comprises at least one of an electroencephalogram parameter, a magnetoencephalogram parameter, a pupillometry parameter, a computer interaction parameter, a heart rate parameter, a respiration rate parameter, or a blood pressure parameter; and wherein the signaling device comprises a sensor configured to sense the completion of the at least one cognitive task parameter.

22. The system of claim 21, wherein the sensor comprises at least one of one or more electrodes, a super-conducting quantum interference device, a camera, LiDAR, a microphone, a force plate, a touch screen, a mouse, a keyboard, a button, a pulse oximeter, or a flowmeter.

23. The system according to any one of claims 1-11, wherein the signaling device is configured to send the signal to the controller upon a memory task being completed by the subj ect, the memory task including at least one memory task parameter; wherein the memory task parameter comprises at least one of an electroencephalogram parameter, a magnetoencephalogram parameter, a polysomnogram parameter, a task completion parameter, a computer interaction parameter, a heart rate parameter, a heart rate variability parameter, a respiration rate parameter, or a blood pressure parameter; and wherein the signaling device comprises a sensor, wherein the sensor comprises at least one of one or more electrodes, a super-conducting quantum interference device, an accelerometer, a microphone, thermal, a touch screen, a mouse, a keyboard, a button, a force plate, a pulse oximeter, or a flowmeter.

24. The system according to any one of claims 1-11, wherein the signaling device is configured to send the signal to the controller upon a biomarker of global cognitive function associated with the subject, the biomarker of global cognitive function including at least one biomarker of global cognitive function parameter;wherein the biomarker of global cognitive function parameter comprises at least one of an electroencephalogram parameter, a magnetoencephalogram parameter, a polysomnogram parameter, a task completion parameter, a computer interaction parameter, a heart rate parameter, a heart rate variability parameter, a respiration rate parameter, or a blood pressure parameter; and wherein the signaling device comprises a sensor configured to sense the biomarker of global cognitive function parameter.

25. The system of claim 24, wherein the sensor comprises at least one of one or more electrodes, a super-conducting quantum interference device, an accelerometer, a camera, LIDAR, a microphone, a force plate, a touch screen, a mouse, a keyboard, a touchpad, a pulse oximeter, or a flowmeter.

26. An earpiece comprising: a body configured to removably couple to an ear of a subject, the body including a first portion; a stimulating electrode coupled to the first portion of the body and configured to contact a cymba concha of the ear when the body is coupled to the ear, the stimulating electrode in communication with a pulse generator and configured to receive a pulse train from the pulse generator such that the stimulating electrode applies transcutaneous stimulation to an auricular branch of a vagus nerve of the ear; and a return electrode coupled to the body.

27. The earpiece of claim 26, wherein the pulse generator is coupled to the earpiece, wherein the pulse train is a biphasic or monophasic such that the stimulating electrode applies bilateral or unilateral current in an auricle of the ear.

28. The earpiece of claim 27, further comprising a microcontroller coupled to the body of the earpiece, the microcontroller having an input and an output, the input of the microcontroller in communication with a signaling device and configured to receive a signal from the signaling device, the output of the microcontroller in communication with the pulse generator andconfigured to cause the pulse generator to send the pulse train to the stimulating electrode in response to the microcontroller receiving the signal from the signaling device.

29. The earpiece of claim 26, wherein the body comprises a second portion extending from the first portion, the return electrode coupled to the second portion and configured to contact a cavum concha of the ear when the body is removably coupled to the ear.

30. The earpiece of claim 29, wherein the stimulating electrode is a first electrode, the earpiece further comprises a second stimulating electrode coupled to the second portion of the body.

31. The earpiece of claim 26, wherein the body comprises a second portion and a third portion, the second portion extending from the first portion of the body and configured to contact a cavum concha of the ear when the body is removably coupled to the ear, the third portion extending from the second portion of the body, the third portion configured to wrap behind an auricle of the ear when the body is coupled to the ear.

32. The earpiece of claim 31, wherein the return electrode is coupled to the second portion, the return electrode configured to contact an antitragus of the ear.

33. The earpiece of claim 31, wherein the return electrode is coupled to the third portion, the return electrode configured to contact a posterior side of the auricle of the ear.

34. The earpiece of claim 26, further comprising a first magnet and a second magnet, the first magnet positioned on an anterior side of the body, the second magnet positioned on a posterior side of body, a magnetic force between the first magnet and the second magnet causing an increase in applied force to the ear by at least one of the stimulating electrode or the return electrode.

35. A computer program stored on one or more tangible, non-transitory, computer-readable storage media having executable instructions for performing the computer program on a computing system, the computer program comprising:receiving a first signal from a signaling device, the first signal associated with an action of a subject; upon receiving the first signal from the signaling device, sending a second signal to a stimulator in communication with the signaling device to actuate according to at least one stimulation parameter for stimulating an auricular branch of a vagus nerve in an ear of the subject.

36. The computer program of claim 35, wherein the signaling device includes an electrical circuit having a state of electrical connection, the state of electrical connection including an open state and a closed state, wherein a change in the state of electrical connection causes the signaling device to send the first signal.

37. The computer program of claim 35, wherein the signaling device includes a sensor configured to detect a parameter associated with the subject, wherein the signaling device sends the first signal when the sensor detects a value of the parameter.

38. The computer program of claim 35, wherein actuation of the stimulator provides electrical stimulation in an auricle of the ear of the subject.

39. The computer program of claim 38, wherein the electrical stimulation is bilateral or unilateral current.

40. The computer program of claim 38, wherein the at least one stimulation parameter comprises biphasic or monophasic pulse trains.

41. The computer program of claim 38, wherein the at least one stimulation parameter comprises providing electrical stimulation with: an amplitude within a range of about 0 - 5.0 mA; a frequency within a range of about 1 - 150 Hz; a pulse width within a range of about 50 - 750 ps; and an impedance within a range of about 500 - 15,000 □.

42. The computer program of claim 35, wherein actuation of the stimulator provides at least one of electrical, thermal, vibrational, or optical stimulation.

43. A method for reducing the progression of, preventing, and / or reducing demyelination in a subject having a demyelination disease, disorder, or condition, the method comprising: transcutaneously stimulating the auricular vagus nerve of the subject.

44. The method of claim 43, wherein the auricular vagus nerve of the subject is stimulated at a cymba concha of an ear of the subject.

45. The method of claim 44, wherein stimulation is provided by an earpiece configured to deliver at least one of electrical stimulation, mechanical-vibration stimulation, ultrasound stimulation, thermal stimulation, or optical stimulation to the cymba concha of the ear of the subject.

46. The method of claim 43, further comprising having the subject perform at least one motor learning task.

47. The method of claim 46, wherein stimulating the auricular vagus nerve of the subject occurs in response to the subject correctly performing the at least one motor learning task.

48. The method of claim 46, wherein stimulating the auricular vagus nerve of the subject only occurs in response to the subject correctly performing the at least one motor learning task.

49. The method of claim 43, wherein the subject comprises a subject having at least one of multiple sclerosis (MS), stroke, spinal cord injury, post-COVID syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), autism, cerebral palsy, treatment-resistant depression, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis (ALS), chronic inflammatory demyelinating polyneuropathy (CIDP), Batten disease, acute disseminated encephalomyelitis (ADEM), acute optic neuritis (AON), transverse myelitis, Neuromyelitis optica spectrum disorders (NMO); cranial neuropathies, autonomic neuropathies or other neuropathycausing demyelination, traumatic brain injury (TBI), side effects of a brain injury, accident or a concussion.

50. A method of promoting remyelination through oligodendrocyte recovery in a subject having a central nervous system, the method comprising: transcutaneously stimulating the auricular vagus nerve of the subject.

51. The method of claim 50, further comprising promoting the growth of new myelin sheaths around axons of the central nervous system of the subject.

52. The method of claim 50, wherein the auricular vagus nerve of the subject is stimulated at a cymba concha of an ear of the subject.

53. The method of claim 52, wherein stimulation is provided by an earpiece configured to deliver at least one of electrical stimulation, mechanical-vibration stimulation, ultrasound stimulation, thermal stimulation, or optical stimulation to the cymba concha of the ear of the subject.

54. The method of claim 50, further comprising having the subject perform at least one motor learning task.

55. The method of claim 54, wherein stimulating the auricular vagus nerve of the subject occurs in response to the subject correctly performing the at least one motor learning task.

56. The method of claim 54, wherein stimulating the auricular vagus nerve of the subject only occurs in response to the subject correctly performing the at least one motor learning task.

57. The method of claim 54, wherein the subject comprises a subject having at least one of multiple sclerosis (MS), stroke, spinal cord injury, post-COVID syndrome, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), autism, cerebral palsy, treatment-resistant depression, post -traumatic stress disorder (PTSD), schizophrenia, anxiety, Alzheimer's disease,Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis (ALS), chronic inflammatory demyelinating polyneuropathy (CIDP), Batten disease, acute disseminated encephalomyelitis (ADEM), acute optic neuritis (AON), transverse myelitis, Neuromyelitis optica spectrum disorders (NMO); cranial neuropathies, autonomic neuropathies or other neuropathy causing demyelination, traumatic brain injury (TBI), side effects of a brain injury, accident or a concussion.

58. The earpiece of claim 26, wherein the body comprises a pinch piece to which a pinch force is applied to insert the earpiece into the ear of the subject.

59. The earpiece of claim 58, wherein the pinch piece comprises a deformable material.

60. The earpiece of claim 58, wherein the pinch piece applies an outward force once inserted into the ear to maintain placement within the ear.

61. The earpiece of claim 58, wherein the body is a C-shape.

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