Transcutaneous auricular vagus nerve stimulation for reinforcement learning

Abstract

The present disclosure provides a reinforcement learning method. The method of the present disclosure includes stimulating a cutaneous distribution of a vagus nerve in a subject's ear with a nerve stimulation vibration signal. The method of the present disclosure further includes instructing the subject to perform an activity while the subject's vagus nerve is being stimulated. The method of the present disclosure further includes monitoring one or more statistics of the subject during the subject's activity.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 483,050, filed February 3, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] (Technical field) The present disclosure generally relates to systems and methods for rehabilitating motor function in subjects (patients) with movement disorders, enhancing motor function and performance in normal subjects, or enhancing memory and learning function in cognitively impaired or normal subjects. [Background technology]

[0003] Approximately 800,000 people in the United States suffer a stroke annually, and over 50% of these suffer long-term upper limb motor impairments six months after the stroke. While numerous stroke rehabilitation strategies already exist, at least some barriers remain that limit patients' ability to improve. Many stroke rehabilitation strategies assume that patients have substantial residual motor function and are therefore ineffective for patients with severe or complete hemiplegia. Furthermore, most approaches do not utilize the patient's own neuronal activity, limiting their ability to maximize central plasticity.

[0004] Vagus nerve stimulation (VNS) has emerged as a tool to promote and accelerate neuroplasticity in both healthy and injured brains, in part due to the release of neuromodulators that promote plasticity at the cellular level. The vagus nerve is a mixed-fiber nerve that influences many upstream cortical and subcortical structures. Noninvasive transcutaneous auricular vagus nerve stimulation (taVNS) has been demonstrated to improve functional recovery after stroke. Despite promising preclinical and clinical results, the neural response to noninvasive VNS and the mechanisms by which it influences motor function recovery remain poorly understood in humans. This has limited the progress of stroke rehabilitation strategies. Clear characterization of the neural response to VNS is crucial for applying this approach to large chronic stroke populations. Vagus nerve stimulation has also been shown to contribute to enhanced cognitive functions, such as memory performance, in human subjects. This is likely due, in part, to activation of key memory-related brain regions, such as the hippocampus and amygdala.

[0005] Conventional techniques for transcutaneous auricular vagus nerve stimulation deliver surface electrical stimulation to the region of the ear innervated by the auricular branch of the vagus nerve. However, due to the electrical nature of surface electrical stimulation, not all subjects can tolerate the stimulation, and in some cases, the subject experiences discomfort or pain. Additionally, a critical factor in electrical stimulation is impedance (i.e., the quality of electrical contact between the electrodes and the skin). Due to heterogeneity in ear shape and size across the population, impedance can vary significantly between individuals, potentially affecting the quality and magnitude of electrical stimulation. Therefore, a need exists for a method to provide consistent stimulation of the vagus nerve. Summary of the Invention [Means for solving the problem]

[0006] In a first aspect of the present disclosure, a reinforcement learning method is provided. The method of the present disclosure includes stimulating a cutaneous distribution of a vagus nerve in a subject's ear with a nerve stimulation vibration signal. The method of the present disclosure further includes instructing the subject to perform an activity while the subject's vagus nerve is being stimulated. The method of the present disclosure further includes monitoring one or more statistics of the subject during the subject's activity.

[0007] In a second aspect of the present disclosure, a system for reinforcement learning is provided. The system of the present disclosure includes a vibrotactile stimulator having at least one form factor. The vibrotactile stimulator is configured to provide vibrations that stimulate a subject's vagus nerve with a vibrotactile signal during an activity. The vibrotactile stimulator is configured to provide vibrations that stimulate the subject's vagus nerve with a vibrotactile signal during the subject's activity. The vibrotactile signal is configured to stimulate a cutaneous distribution of the vagus nerve in the subject's ear with a nerve stimulation signal. [Brief explanation of the drawings]

[0008] Those skilled in the art will appreciate that the drawings described below are for illustrative purposes only and are not intended to limit the scope of the present teachings in any way.

[0009] [Figure 1] FIG. 1 illustrates a system for providing vagus nerve stimulation to a subject, according to one embodiment of the present disclosure. [Figure 2A] 2A-2F illustrate exemplary form factors for providing non-invasive transcutaneous auricular vagus nerve stimulation using the system shown in FIG. [Figure 2B] 2A-2F illustrate exemplary form factors for providing non-invasive transcutaneous auricular vagus nerve stimulation using the system shown in FIG. [Figure 2C] 2A-2F illustrate exemplary form factors for providing non-invasive transcutaneous auricular vagus nerve stimulation using the system shown in FIG. [Figure 2D]2A-2F illustrate exemplary form factors for providing non-invasive transcutaneous auricular vagus nerve stimulation using the system shown in FIG. [Figure 2E] 2A-2F illustrate exemplary form factors for providing non-invasive transcutaneous auricular vagus nerve stimulation using the system shown in FIG. [Figure 2F] 2A-2F illustrate exemplary form factors for providing non-invasive transcutaneous auricular vagus nerve stimulation using the system shown in FIG. [Figure 3] FIG. 3 illustrates a method for providing vagus nerve stimulation to a subject using the system shown in FIG. [Figure 4] FIG. 4 illustrates an exemplary configuration of the client system shown in FIG. 1 according to one embodiment of the present disclosure.

[0010] While the drawings show the configuration currently being described, it should be understood that the present embodiments are not limited to the configuration shown, but are by way of illustration. While various embodiments are disclosed, still other embodiments of the present invention will become apparent to those skilled in the art from the following detailed description illustrating illustrative aspects of the present disclosure. As will be understood, the present invention is capable of modification in various aspects without departing from the spirit and scope of the present invention. Accordingly, the drawings and detailed description should be regarded as illustrative in nature and not restrictive. DETAILED DESCRIPTION OF THE INVENTION

[0011] Various embodiments of the present disclosure provide devices and methods for providing vagus nerve stimulation (VNS) to a subject (patient). Non-invasive vagus nerve stimulation is desirable because direct vagus nerve stimulation is invasive. In some embodiments, the non-invasive vagus nerve stimulation device may be any known non-invasive vagus nerve stimulation device, including, but not limited to, electrical stimulation, vibration, or ultrasound methods for activating the vagus nerve. However, for purposes of this disclosure, the non-invasive vagus nerve stimulation device of the present disclosure applies vibrotactile stimulation to a subject. A non-limiting example of a non-invasive vagus nerve stimulation device suitable for use in the systems and methods of the present disclosure includes a transcutaneous auricular vagus nerve stimulation (taVNS) device.

[0012] Because electrical non-invasive vagus nerve stimulation is problematic, the disclosed systems and methods deliver vibrotactile stimulation to the outer ear to stimulate the vagus nerve.

[0013] The disclosed devices deliver vibrotactile stimulation to the region of the ear innervated by the auricular branch of the vagus nerve. In some embodiments, the disclosed devices do not require user intervention after placement or the need to hold the device in place during stimulation. This advantage eliminates the potential for user error and inherent subjectivity regarding pressure that may exist with alternative means of delivering vibration to the ear. For example, a critical factor in electrical stimulation is impedance (i.e., the quality of electrical contact between the electrodes and the skin). Due to heterogeneity in ear shape and size across the population, impedance can vary significantly between individuals, potentially having an undesirable effect on the quality and magnitude of electrical stimulation.

[0014] To address these factors, the present inventors have developed a novel device for delivering vibrotactile stimulation to the region of the ear innervated by the auricular branch of the vagus nerve. The disclosed device requires no user intervention after placement and no need to hold the device in place during stimulation, eliminating the possibility of user error and the inherent subjectivity of pressure. The disclosed vibrotactile stimulation device induces brain changes consistent with activation of brain regions (e.g., the hippocampus) that play a key role in learning. The disclosed vibrotactile stimulation device and method are easy to apply and can be combined with stimuli to enhance learning because they activate the hippocampus. Examples include combining vibrotactile stimulation with educational digital content. Examples include, but are not limited to, (1) digital flashcards to assist in learning new information, (2) educational materials for individuals with learning disabilities (e.g., specialized reading materials for dyslexia), and / or (3) digital representations of social situations, phobia-related content, and human interactions to support individuals with autism, phobias, and PTSD. The vibrotactile stimulator of the present disclosure can also be used in combination with a motor interactive device that can promote motor learning in the context of motor training and / or motor rehabilitation (such as for stroke or spinal cord injury). Additionally, stimulation by the vibrotactile stimulator can also be used to provide sound therapy for tinnitus.

[0015] In some embodiments, transcutaneous stimulation of the auricular branch of the vagus nerve is performed using a vibrotactile stimulation device that provides vibrations to stimulate the vagus nerve via the subject's ear. Without being limited to a particular theory, the pinna, which is innervated by the auricular branch of the vagus nerve, is an effective location for non-invasive stimulation of the vagus nerve. In one embodiment, an ear clip used for auricular vagus nerve stimulation (VNS) is positioned along the concha. In another embodiment, a device of the present disclosure includes a vibration device, a power source, electronics, and a wearable form factor, and is configured to be secured to the subject's ear.

[0016] In some embodiments, the vibrotactile stimulator of the present disclosure is integrated into a wearable ear device, such as an earphone, that facilitates learning and eases access to auditory content.

[0017] In some embodiments, the disclosed vibrotactile stimulator is used in conjunction with video game play to enhance game performance. This includes incorporating the disclosed vibrotactile stimulator into a head-mounted system (e.g., a headset or earphones) associated with the video game. Alternatively, the disclosed vibrotactile stimulator may be independent of a wearable headset system. Ear stimulation with the disclosed vibrotactile stimulator can improve a video game player's working memory, attention, reaction time, alertness, and motor learning, all of which are related to improving a video game player's performance. This can improve a player's performance in a given video game or in a competitive video game. A video game player's performance can be monitored during vibrotactile stimulation, and based on their performance, parameters of the vibrotactile stimulator stimulation can be adjusted. Such parameter adjustments can be performed by the gamer, the video game, or a machine learning algorithm that automates the updates. Parameter adjustments can include changes to stimulation duration, timing based on game parameters and experience, and frequency and intensity of vibrotactile stimulation. The disclosed devices can be associated with software that provides metrics and usage suggestions regarding the relationship between video game performance and vibrotactile stimulation. Examples of video games include multiplayer video games, flight simulators, first-person shooter video games, racing video games, athletic or sports simulation games, and / or strategy games. Similarly, other computer-mediated interactions can be enhanced or modified through human-to-human video presence or virtual reality.

[0018] A further embodiment is the use of vibrotactile stimulation to enhance preparation for standardized tests. Vibrotactile stimulation can be provided through physical materials such as books and note cards, or through learning modules provided by software that provide practice tests, note cards, tutoring, explanations, strategies, etc. Subject performance can be monitored before, during, and after stimulation, and parameters can be adjusted or test-taking performance can be monitored. The disclosed methods can also be applied to general education using distance learning. Stimulation can be provided while students are receiving instruction or taking practice tests.

[0019] In various embodiments, transcutaneous auricular vagus nerve stimulation (VNS) performed by a non-invasive vagus nerve stimulator is configured to improve a subject's behavioral motor performance. Without being limited to a particular theory, VNS is believed to modify a subject's brain activity to improve the subject's motor learning and / or motor performance. As a non-limiting example, VNS increases neural activity in brain regions important for motor learning based on anatomical projections from the nucleus tractus solitarius (NTS), where vagus nerve fibers terminate. Non-limiting examples of anatomical projections from the nucleus tractus solitarius (NTS) related to motor learning include the amygdala, hippocampus, and prefrontal cortex. In various embodiments, the increased neural activity is characterized as an increase in low-frequency coherence in brain regions receiving input from the nucleus tractus solitarius (NTS).

[0020] In various embodiments, the delivered vagus nerve stimulation is characterized by VNS parameters, such as stimulation frequency and amplitude. The VNS parameters may be any suitable value without limitation. In some embodiments, the stimulation frequency ranges from about 1 Hz to about 120 Hz. In some embodiments, the stimulation frequency is selected from 6 Hz, 20 Hz, 30 Hz, 40 Hz, and 120 Hz.

[0021] The disclosed system and method introduces vibratory stimulation of the vagus nerve as a practical method for enhancing working memory. This finding indicates that application of vibrotactile taVNS is most beneficial to working memory performance when cognitive load is close to working memory capacity. Mechanistically, vibrotactile taVNS rescues the decline in arousal that occurs during continuous utilization of working memory. Additionally, vibrotactile taVNS increases arousal levels to a level optimal for working memory performance.

[0022] In various embodiments, the disclosed system is used in a method for rehabilitating motor function in a subject (patient) with a motor dysfunction. The disclosed method includes providing a brain-computer interface (BCI) similar to the device described above and a non-invasive vagus nerve stimulation device. The disclosed method also includes providing a motor rehabilitation therapy to the subject using the BCI. The disclosed method also includes, at least as part of the motor rehabilitation therapy, administering vagus nerve stimulation (VNS) to the subject configured to enhance the subject's behavioral motor performance.

[0023] The disclosed system and method further improves functional recovery in chronic stroke patients by combining noninvasive VNS with BCI-driven rehabilitation techniques. In the disclosed examples, optimal taVNS parameters for enhancing motor learning were determined through invasive recording of cortical physiology. Without being limited to a particular theory, it is believed that taVNS contributes to increased brain activity and improved coherence, which promotes widespread connectivity, thereby contributing to enhanced motor learning. The disclosed system and method provide a mechanism-driven approach for the design, optimization, and clinical application of taVNS rehabilitation methods for motor recovery in chronic stroke. Based on promising findings from invasively recorded nonhuman primate and human behavioral data described in the disclosed examples, optimal taVNS parameters for increasing neuronal coherence in invasively monitored human subjects are determined, and the neurophysiology of taVNS-associated motor learning effects is defined. The effects of various stimulation parameters (stimulation frequency, pulse width, and current intensity) on the subject's brain activity are systematically evaluated.

[0024] In various embodiments, devices and treatment methods are provided for rehabilitating motor function in a subject with a motor impairment. The subject's motor impairment may be due to, but is not limited to, any known injury, disease, or disorder associated with motor impairment. Non-limiting examples of injuries, diseases, or disorders that can be rehabilitated using the systems and methods of the present disclosure include stroke, such as unilateral stroke, spinal cord injury, neuromuscular disorder, traumatic brain injury, limb amputation, peripheral nerve injury, and any other associated motor impairment.

[0025] In various embodiments, the BCI device of the present disclosure may be any suitable device suitable for administering motor function restoration therapy to a subject with a motor dysfunction, including, but not limited to, an assistive BCI device configured to restore lost function in a subject. Non-limiting examples of lost function that can be restored using an assistive BCI device include communication in locked-in syndrome (e.g., due to amyotrophic lateral sclerosis), movement in paralysis, and eating and drinking despite quadriplegia using robotic actuators and / or functional electrical stimulation systems. In other embodiments, the BCI device may be a rehabilitation BCI device configured to promote neuroplasticity through the manipulation or autoregulation of neurophysiological activity using neurofeedback to promote motor recovery. In some embodiments, the BCI device converts electrical, magnetic, or metabolic brain activity into control signals for external devices that can replace, restore, enhance, supplement, or improve natural neural output, thereby modifying the ongoing interaction between the brain and its external or internal environment. Non-limiting examples of BCI devices suitable for use in the systems and methods of the present disclosure are described in U.S. Patent Nos. 9,730,816 and 10,596,014, and U.S. Patent Application Publication No. 2020 / 0188139, the entire disclosures of which are incorporated herein by reference. In various embodiments, the BCI device can be, but is not limited to, any device suitable for providing motor rehabilitation therapy to a subject with a movement disorder.

[0026] Outside of motor rehabilitation, these taVNS techniques can be used to improve motor function in neurologically normal human subjects. Specifically, taVNS can be used during the performance of motor tasks that require significant repetition to master. Examples include athletic activities (sports), musical activities, medical activities such as surgery, work-related activities, or any complex movement. Examples of athletic activities include, but are not limited to, basketball, tennis, baseball, golf, running, volleyball, badminton, swimming, boxing, table tennis, skiing, ice skating, roller skating, cricket, rugby, pool, darts, football (soccer), bowling, ice hockey, surfing, martial arts, horse racing, snowboarding, skateboarding, cycling, archery, fishing, gymnastics, figure skating, rock climbing, sumo wrestling, wrestling, fencing, water skiing, jet skiing, weightlifting, scuba diving, snorkeling, windsurfing, skydiving, hang gliding, and bungee jumping. Examples of musical activities include, but are not limited to, playing an instrument, dancing, theatrical performances, ballet, opera, and singing. Examples of medical activities include, but are not limited to, performing surgical procedures, clinical procedures, diagnostic procedures, and physical examinations. Examples of work-related activities include, but are not limited to, technical work (e.g., electrical work, plumbing, carpentry), and manual labor (e.g., construction work, welding, roofing, and / or other physical labor). In other embodiments, the activity may be a mental learning activity, such as memorization (e.g., using flash cards), learning mathematics, practicing public speaking, and / or other learning activities.

[0027] Furthermore, in some embodiments, vibrotactile taVNS can also be used to improve working memory through neuromodulation of arousal pathways. For example, vibrotactile taVNS delivered to the concha significantly improves performance on the 4-back task, which utilizes maximal working memory. Arousal, as measured by skin conductance and pupil diameter, typically declines as the task progresses. However, vibrotactile taVNS significantly reverses this decline in arousal, increasing arousal levels to those corresponding to optimal working memory levels. Furthermore, vibrotactile taVNS delivered to the concha increases pupil diameter and skin conductance levels during high cognitive load tasks.

[0028] The definitions and methods set forth herein are provided to better define the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. Unless otherwise specified, terms should be understood according to conventional usage by those of ordinary skill in the art.

[0029] In some embodiments, numbers expressing quantities of ingredients, properties (e.g., molecular weight), reaction conditions, and the like, used to describe and claim particular embodiments of the present disclosure, should be understood to be modified in some instances by the term "about." In some embodiments, the term "about" is used to indicate that a value includes the standard deviation of the average for the device or method being employed to determine that value. In some embodiments, the numerical parameters set forth in the specification and appended claims are approximations that can vary depending on the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as practicable. The numerical values ​​set forth in some embodiments of the present disclosure may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if each individual value were individually set forth in the specification. References to discrete values ​​are understood to include ranges between the values.

[0030] In some embodiments, the terms "a," "an," "the," and similar terms used in the context of describing particular embodiments (particularly in the particular context of the claims below) can be construed to encompass both the singular and the plural, unless otherwise indicated. In some embodiments, the term "or" as used herein, including in the claims, refers to alternatives only, or is used to mean "and / or," unless the alternatives are expressly stated to be mutually exclusive.

[0031] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur.

[0032] The terms "comprise," "have," and "include" are open-ended linking verbs. Any variation or tense of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes," and "including," are also open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps and may include other unrecited steps. Similarly, any composition or device that "comprises," "has," or "includes" one or more features is not limited to having only those one or more features and may include other unrecited features.

[0033] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any and all examples provided with respect to specific embodiments herein, or the use of exemplary language (e.g., "etc."), are intended merely to better clarify the disclosure and do not impose limitations on the scope of the invention unless specifically recited in the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0034] Groupings of alternative elements or embodiments of the disclosure disclosed herein are not to be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements described herein. One or more members of a group may be included in or deleted from a group for reasons of convenience or patentability. When such inclusion or deletion is made, the specification is deemed to include the modified group and, therefore, satisfies all Markush group descriptions used in the appended claims.

[0035] All publications, patents, patent applications, and other documents cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each was specifically and individually indicated to be incorporated by reference. The citation of a document herein should not be construed as an admission that it is prior art to the present disclosure.

[0036] Although the present disclosure has been described in detail, it will be apparent that modifications, variations, and equivalents are possible without departing from the scope of the present disclosure as defined in the appended claims. Furthermore, it should be understood that all examples in this disclosure are provided as non-limiting examples.

[0037] FIG. 1 illustrates a system 100 for providing vagus nerve stimulation to a subject (patient) according to at least one embodiment.

[0038] A recent trend in neuromodulation therapy is the use of vagus nerve stimulation (VNS) as a means of promoting neuroplasticity. The vagus nerve is composed of 80% afferent and 20% efferent fibers. It is the primary visceral sensory nerve and innervates many organs in the body. Vagus nerve stimulation is typically performed using a cuff electrode surgically implanted within the left carotid sheath, surrounding the left vagus nerve. The cuff electrode is connected to a pulse generator implanted on the left side of the subject's chest. The left vagus nerve is used because it has fewer efferent fibers descending to the heart than the right vagus nerve, making it safer to stimulate. VNS has proven effective as a treatment for intractable epilepsy and treatment-resistant depression, and in recent years it has also been investigated as a treatment for neurological injuries such as stroke and traumatic brain injury.

[0039] The vagus nerve has a direct ascending projection to the nucleus tractus solitarius (NTS) and is known to activate the locus coeruleus (LC) and nucleus basalis (NB). The LC (located in the pons) and NB (located in the basal forebrain) are part of a neuromodulatory system with widespread projections throughout cortical and subcortical regions. The LC contains noradrenergic neurons (norepinephrine: NE), and the NB contains cholinergic neurons (acetylcholine: ACh), both of which are known to be neuromodulators that promote plasticity. The release of NE and ACh is important in processes such as arousal, memory encoding, and task-engagement, as well as processes requiring high attentional load. Therefore, NE and ACh may play an important role in the mechanism of action of rehabilitation involving goal-directed behaviors in combination with VNS.

[0040] VNS stimulation induces the release of neuromodulators NE and ACh, resulting in changes in cortical plasticity. This change in cortical plasticity is believed to mediate therapeutic effects. Specifically, VNS has been shown to reorganize the auditory or motor cortex in rats, and in combination with VNS, it has been shown to increase cortical recall of speech or movement. This is supported by lesion studies showing that reducing NE or ACh concentrations inhibits cortical plasticity and results in learning deficits. VNS, when applied at moderate intensities, has the ability to improve recognition memory in humans. Furthermore, when applied during the memory consolidation phase, VNS has been shown to improve memory retention on the Hopkins Verbal Learning Test and enhance working memory, as evidenced by reduced error rates on executive function tasks.

[0041] While invasive VNS has been studied for decades, noninvasive stimulation of the vagus nerve, particularly the auricular branch, which innervates the concha and tragus regions of the external ear, has emerged as a promising noninvasive alternative. Transcutaneous transauricular vagus nerve stimulation (taVNS) offers the distinct advantage of eliminating the need for invasive surgery and reducing the potential side effects associated with implanted devices. Several functional magnetic resonance imaging (fMRI) studies have demonstrated that taVNS has similar central effects to invasive VNS. Compared with sham earlobe stimulation, stimulation of the concha navicularis in the left ear was found to induce significant activation of central vagal projections, including the NTS and LC. Another fMRI study compared the concha navicularis and tragus as taVNS stimulation sites and found activation of vagal projections in both, but only the concha navicularis induced significant activation of the NTS and LC compared with sham stimulation. Vagus nerve stimulation via the outer ear, like invasive VNS, has been studied for many similar disorders, including epilepsy, depression, and tinnitus. Furthermore, similar to findings from invasive VNS, taVNS has been shown to improve cognitive function in older adults, including improved verbal category learning and retention of non-native speech categories, as well as enhanced associative memory.

[0042] The system 100 of the present disclosure includes a VNS controller 105. The VNS controller 105 may be a computing device, such as a tablet, laptop computer, desktop computer, or other dedicated computing device having at least one processor capable of communicating with at least one memory device, and includes a user interface that allows the VNS controller 105 to present information to a user and receive user input.

[0043] The VNS controller 105 can communicate with a vibration controller 110 configured to control vibrations for vibrotactile stimulation. In some embodiments, the vibration controller 110 can communicate directly with the first form factor 115 and the second form factor 120 of the system 100 of the present disclosure. The VNS controller 105 can also communicate with one or more vibrating form factors, such as the first form factor 115 and the optional second form factor 120. The first form factor 115 and the second form factor 120 are configured to provide vibrotactile stimulation to a subject. In some embodiments, the system 100 of the present disclosure includes only a single form factor 115. In other embodiments, the first form factor 115 is attached to a first ear of the subject and the second form factor 120 is attached to a second ear of the subject. In an exemplary embodiment, the first form factor 115 and the second form factor 120 are secured to the subject's ear to prevent accidental detachment, yet are easily attached and detached from the subject's ear. In an exemplary embodiment, the first form factor 115 and the second form factor 120 are temporarily attached to a subject's ear to stimulate the vagus nerve.

[0044] In an exemplary embodiment, the first form factor 115 and the second form factor 120 provide stimulation to one or more of the navicularis concha, the concha, and the ear canal. In some embodiments, the first form factor 115 and the second form factor 120 are positioned along the concha, which is innervated by the auricular branch of the vagus nerve, to stimulate the vagus nerve. In an exemplary embodiment, the form factors are attached to the subject's left ear.

[0045] In at least one embodiment, the VNS controller 105 is configured to provide vibration stimulation to the vagus nerve for 20 minutes. In at least one embodiment, one attribute of the vibration stimulation is 6 Hz. The attribute of the vibration stimulation remains the same throughout treatment. In at least one further embodiment, the vibration stimulation is administered twice daily. In at least one embodiment, the attribute of the vibration stimulation is selected to maximize vagal somatosensory evoked potentials while avoiding the perception of pain.

[0046] In an exemplary embodiment, the VNS controller 105 controls the output of the vibration controller 110 to provide vibration stimuli to the subject via the first form factor 115 and the second form factor 120 .

[0047] In some further embodiments, the VNS controller 105 can communicate with one or more user computing devices 125. The user computing devices 125 can provide the VNS controller 105 with one or more attributes of the subject that may modify the vibration stimuli applied to the subject. Additionally, the user computing devices 125 can provide timing information to the VNS controller 105, such as the timing of applying the vibration stimuli. Additionally, the user computing devices 125 can receive information from the VNS controller 105, such as the attributes of the vibration stimuli applied to the subject.

[0048] In some further embodiments, the first form factor 115 is applied to a first subject and the second form factor 120 is applied to a second subject. The VNS controller 105 controls the stimulation applied to each subject simultaneously. In some of these embodiments, the VNS controller 105 controls multiple form factors for multiple subjects to which vibrotactile stimulation is applied.

[0049] The sensor 130 can be used to determine optimal taVNS parameters for enhancing motor learning by recording invasive cortical physiology. taVNS increases gamma wave power, which increases brain activity and arousal, contributing to enhanced learning.

[0050] In some embodiments, the sensor 130 includes a stereotactic electroencephalogram (sEEG). The sensor 130 can be used to monitor the effect of stimulation parameters on the subject's brain activity, particularly during motor or memory tasks. During these tasks, the sensor 130 reports the effect of stimulation frequency, etc., on the subject's brain activity. This allows for optimal parameters to be identified and / or tailored to the individual subject. In at least one embodiment, the parameter monitoring can be performed by monitoring the subject while they are engaged in a motor learning task paradigm (e.g., serial reaction time task, SRTT). In another embodiment, the parameter monitoring can be performed by monitoring the subject while they are engaged in a memory-based task. The sensor 130 can also be used to monitor the subject's response and other attributes (e.g., but not limited to, arousal state, behavioral response, skin conductance, and / or eye tracking). The user computing device 125 can collect electrophysiological, behavioral, and kinematic data to fully characterize the effect of taVNS on motor or memory learning. Other sensors 130 include, but are not limited to, sensors for measuring temperature, brainwave activity, galvanic skin response, blood pressure, heart rate, and / or any other attribute or statistic of the subject.

[0051] In at least one embodiment, the disclosed system 100 has a form factor that includes ear cups, a cushion base that provides soft contact with the head, and a T-head bolt that connects the contact tips and ear cups via the ear cup covers. In this embodiment, a vibration controller 110 controls a 5 mm diameter eccentric rotating mass (ERM) vibration motor held at the contact tips. The motor's power cable passes through the T-head bolt. The T-head bolt allows for individual adjustment of contact depth. Additionally, rotating the T-head bolt allows for switching the stimulation target between the concha and the earlobe. A digital stimulation box provides 5 V of power (e.g., 6 Hz) to the eccentric rotating mass vibration motor. Studies aimed at characterizing locus coeruleus (LC) responses to VNS have found that LC activity increases in response to stimulation frequencies ranging from 7.5 Hz to 120 Hz, with maximum discharge increasing at higher stimulation frequencies. Because LC activity and task performance have an inverted U-shaped relationship, a 6 Hz vibrotactile taVNS frequency was selected to increase LC activity without exceeding optimal values. The vibrotactile stimulator was secured to the subject's head with an elastic strap. During the VNS session, vibrotactile stimulation was delivered to the concha region of the outer ear.

[0052] 2A-2F illustrate exemplary form factors 115 (see FIG. 1) for non-invasive transcutaneous auricular vagus nerve stimulation using the system 100 (see FIG. 1) of the present disclosure. In FIG. 2A, the form factor 115 is secured in place on the subject's (user's) head using a headband. In FIG. 2B, the form factor 115 is an ear clip and is attached to the subject's ear. In FIG. 2C, the form factor 115 is an ear hook and is attached to the subject's ear. In FIG. 2D, the form factor 115 used is a headset with an integrated vibration generator that covers the subject's ear. In FIG. 2E, the form factor 115 used is custom molded to fit a specific subject's ear. Custom molded form factors may include moldable modeling clay and / or wax. In some of these embodiments, the vibration generator is covered with this moldable material. In FIG. 2F, the form factor 115 is an ear hook with a concha navicular stimulation portion and an ear canal stimulation portion.

[0053] FIG. 3 illustrates a method 300 for providing vagus nerve vibration stimulation to a subject using the system 100 illustrated in FIG. 1. In an exemplary embodiment, portions of the disclosed method 300 are performed by a user computing device 125 (see FIG. 1). The user computing device 125 may be, but is not limited to, a tablet, a laptop computer, a desktop computer, and / or other computing device including at least one processor capable of communicating with at least one memory device. Additionally, portions of the disclosed method 300 are performed by the VNS controller 105 and / or the vibration controller 110 (see FIG. 1).

[0054] In an exemplary embodiment, the user computing device 125 controls the vibration controller 110 to administer vibration stimulation to the subject (step 320). During a VNS session, vibrotactile stimulation is delivered to the concha region of the outer ear. In at least one embodiment, the vibrotactile stimulation is applied at a default frequency of 6 Hz.

[0055] In an exemplary embodiment, the user computing device 125 first receives subject attributes (hereinafter referred to as "subject attributes") (step 305). The subject attributes may be obtained from the subject when the subject visits the clinic or by searching the subject's history. The subject attributes may include, but are not limited to, height, weight, gender, heart rate, blood pressure, medical history, blood test results, vital statistics, presence / location of aneurysms on angiography, motion limitations, and other attributes. The subject attributes may also include CT (computed tomography) images of neural tissue damaged by stroke. The subject attributes are then analyzed (step 310), and parameters for taVNS vibrotactile stimulation are generated based on the subject attributes (step 315).

[0056] In an exemplary embodiment, the user computing device 125 generates appropriate parameters for the taVNS vibrotactile stimulation based on the analysis results for the plurality of subjects, their responses to the taVNS vibrotactile parameters, and their subject attributes (step 315). In some embodiments, the user computing device 125 trains an artificial intelligence and / or machine learning model based on historical data for the plurality of subjects. In some of these embodiments, the model also includes historical information for the current subject based on past vibrotactile stimulation sessions.

[0057] The system 100 of the present disclosure applies vagal nerve vibrotactile stimulation to the subject (step 320). In some embodiments, the subject controls the vibrotactile stimulation session. In other embodiments, the vibrotactile stimulation session is provided by another individual, such as, but not limited to, a healthcare professional. A first form factor 115 (see FIG. 1 ) is attached to the subject. In some embodiments, both the first form factor 115 and the second form factor 120 are attached to the subject. In an exemplary embodiment, the first form factor 115 is attached to the concha of the subject's left ear, as shown in FIGS. 2A-2F. The VNS controller 105 then provides vibrations to the subject via the first form factor 115 and the second form factor 120. In an exemplary embodiment, the frequency of the vibrations is 6 Hz. The frequency of the vibrations can range from 1 Hz to 200 Hz, or any other value, depending on the vibrotactile stimulation session. Additionally, other attributes of the frequency can be varied depending on other factors, such as subject attributes. In some embodiments, the vibrotactile stimulation is maintained at the same attributes for the entire duration of the stimulation, while in other embodiments, the vibrotactile stimulation begins at a lower frequency and the VNS controller 105 increases the frequency over time.

[0058] The sensor 130 measures the subject's response to the vibration stimulation (step 325). Measurements of the subject's response may include, but are not limited to, detecting behavioral responses, skin conductance, and eye tracking, and / or any other measurements for monitoring the subject's response during the vibrotactile session. The user computing device 125 determines whether the subject's response is optimized, for example, whether the subject's alertness is optimized for performing the activity (step 330). If the subject's response is not optimized, the user computing device 125 adjusts the vibration stimulation, such as by increasing the frequency of the vibration controller 110 (step 335). This adjustment continues until the sensor 130 detects that changes in frequency or other conditions based on the desired use of the session no longer change the subject's response. In some embodiments, the sensor 130 is incorporated into the form factor described above so that it can acquire physiological signals in an area adjacent to the area of ​​the ear where the vibrations are delivered.

[0059] Once the subject's response is optimized (step 330), the subject performs an activity (step 340). In some embodiments, the subject performs an activity based on memory and / or learning. In other embodiments, the subject performs a motor function activity using a mechanical device or the like to train some of the subject's muscles and / or other desired responses.

[0060] In at least one example, the activity is performed for up to 20 minutes. During that time, the VNS controller 105 applies vibrotactile taVNS to the subject (step 320) and measures the subject's statistics during the activity (step 345). Once the activity is completed, taVNS is discontinued and the first and second form factors 115 and 120 are removed from the subject. In other embodiments, the activity or exercise regimen is performed for only a few minutes, but the length of treatment is gradually increased over time until the subject is able to handle longer treatments. In other embodiments, the subject may receive treatment on one side of the body, the other side, or both sides, sequentially or simultaneously. In some embodiments, the subject's statistics are monitored after taVNS is discontinued to monitor the return of the statistics to baseline.

[0061] In one example, vibrotactile taVNS can be used in a memory test in which subjects press a button when they determine that the currently presented number is identical to the number presented N trials earlier. In the n-back task, the number displayed is randomly selected from four numbers: 0, 1, 2, and 3. Each subject completed three sessions: a baseline session, a sham session, and a VNS session. The session order was randomly determined before subject recruitment. In the baseline session, subjects completed eight blocks of the n-back task, with n ranging from 1 to 8. Each block contained 40 probes, i.e., presentations of numbers for which the subject had to decide whether to press a button. Before the first probe, N numbers were presented to load the subject's working memory. As numbers continuously appeared on the screen, subjects had to constantly refresh their working memory and decide whether to press a button. In the VNS or sham session, subjects completed eight blocks of the n-back task, with n ranging from 0 to 4. The 0-back task in the VNS or sham session was designed as an attentional control. After the baseline session, subjects were instructed to rest and close their eyes. Data collected from the subjects while their eyes were closed was used to validate the eye-tracking and skin conductance recordings. During the VNS session, vibrotactile stimulation was delivered to the concha region of the outer ear. The earlobe is primarily innervated by the great auricular nerve, which originates from the second and third cervical branches. Therefore, consistent with previous studies, the earlobe was used as a sham stimulation target.

[0062] During these sessions, behavioral responses were recorded by button presses detected with a multimodal trigger box, galvanic skin conductance using a USBAMP research amplifier, and pupillometry using an eye tracker.

[0063] In this example, performance was evaluated using hit rate, false alarm rate, reaction time, and d prime (d'). This refers to the probe, which is the presentation of a number that the subject must decide whether to press a button. Hit rate refers to the proportion of actual positive probes when the subject presses a button, false alarm rate refers to the proportion of actual negative probes when the subject presses a button, and reaction time refers to the difference between the onset of the number presentation and the onset of the button press. d' is a combined measure of hit rate and false alarms, quantifying the subject's ability to distinguish between positive and negative probes. d' is calculated using the following equation (1): where Z is the inverse of the cumulative Gaussian distribution function. d´ = Z(hit rate) - Z(false alarm rate) Equation (1)

[0064] In this example, the sensor 130 records skin conductance at a sampling rate of 1200 Hz and resamples it at 10 Hz for fast processing. The system 100 of the present disclosure uses a 6th-order Butterworth low-pass filter with a cutoff frequency of 2 Hz to smooth the skin conductance and remove high-frequency artifacts. For event-related analysis, skin conductance was normalized to a range of 0 to 1 and synchronized to the task onset of each N-back task block.

[0065] Using a convex optimization approach, skin conductance signals can be decomposed into a tonic component representing general arousal and a phasic component representing sympathetic activity. For comparisons across subjects and sessions, skin conductance levels were sampled every 10 seconds and z-scored based on the value of the 1-back task within each session. To bridge the behavioral and physiological effects of vibrotactile taVNS, the difference in skin conductance levels between sham / VNS and baseline sessions was calculated for each difficulty level. Performance metrics (e.g., d´) were then grouped based on this difference and compared.

[0066] The sensor 135 acquired pupil diameter data at a sampling rate of 120 Hz and a measurement resolution of 0.1 mm. Invalid pupil measurements due to blinking or eye closure were removed. The start and end of a blink were detected when the pupil diameter measurement exceeded a threshold of 0.3 mm / ms. To improve detection accuracy, blink duration was assumed to be no longer than 500 ms. If a blink's end was not detected within 500 ms after its onset, the blink was deemed to have ended 500 ms after the last detected blink. To account for the possibility of incorrect pupil measurements before a blink, a safety margin of 15 ms was added before and after each blink. Finally, the remaining valid pupil measurements were resampled at 30 Hz for further processing.

[0067] To extract the temporal dynamics of pupil diameter under VNS, sham, and baseline conditions, pupil diameters were z-scored to eliminate inter-subject differences. The presentation of numbers and fixation points induced a periodic component in the subject's pupil diameter with a 1.5-second period. To remove this confounding component and extract the general arousal component, a 0.1 Hz low-pass filter was applied to the linearly interpolated pupil diameters. To demonstrate the effect of VNS on general arousal during N-back tasks of varying difficulty, the disclosed system first interpolated and filtered the pre-processed pupil diameters using a 0.1 Hz low-pass filter. The disclosed system then corrected the filtered pupil diameters by subtracting the average filtered pupil diameter during the 1-back task in each session to correct for differences between sessions.

[0068] To identify the dynamic range of task performance, the disclosed system gradually increased N from 1 to 8 during baseline sessions on an N-back task. Hit rates and d' decreased asymptotically as N increased. Reaction times showed a clear increase only when N was changed from 1 to 2. Performance declined as the amount of working memory required to complete the task increased. Thus, as N increased, i.e., as difficulty increased, d' approached a lower bound representing d' when the subject would press the button by chance. A four-parameter log-logistic regression model provided a good fit to d' (mean residual = 0, standard error of residual = 2.5). A t-test showed that d' for n = 3 was significantly higher than the parameter c estimated by the four-parameter log-logistic regression model (t = 2.71, p < 0.01). On the other hand, d' for n = 4 showed no significant difference from parameter c (t = 0.94, p = 0.18). These results indicate that subjects were actively performing the N-back task and that maximum working memory capacity was likely to be highest in the 4-back, which is consistent with research on working memory capacity.

[0069] Performance decreased as N increased to 4, indicating that the working memory capacity required was close to that of the 4-back task. Comparing this to performance on the 4-back task clarified the effect of vibrotactile taVNS on cognitively demanding tasks. A pairwise Wilcoxon test showed that vibrotactile VNS resulted in a 96% improvement in d', calculated as the percent change in mean d' compared to the baseline session (Cohen's d = 0.63, Bonferroni-corrected p < 0.01, n = 20). d' during the sham session was not significantly different from d' during the baseline session (Cohen's d = 0.26, Bonferroni-corrected p > 0.05, n = 20). d' during the VNS session was higher than d' during the sham session, but the difference was not significant (Cohen's d = 0.48, Bonferroni-corrected p > 0.05, n = 20). When N = 4, the increase in d' was not accompanied by an increase in reaction time.

[0070] Linear regression analysis confirmed the effects of vibrotactile taVNS, session, order (instruction), and difficulty on d'. The model with the lowest AIC was a linear mixed-effects model incorporating difficulty, session, order, and the interaction between session and difficulty as fixed effects and a random intercept to account for individual differences. The median of the scaled residuals was 0, with an interquartile range of -0.70 to 0.69. Satterthwaite t-tests revealed significant effects of difficulty, order, the interaction between taVNS and difficulty, and taVNS (see Figure 3c). Specifically, d' decreased as difficulty increased. Importantly, the decrease in d' was smaller during the VNS session, as indicated by a significant positive β_(N:VNS). Furthermore, d' increased in subsequent sessions, as indicated by a positive β_order (see Supplementary Figure 3). A negative β_VNS was observed, indicating that vibrotactile VNS is not beneficial for tasks that do not require maximal working memory. For reaction times, the model with the lowest AIC includes difficulty, session, order, and difficulty as fixed effects, and a random intercept to account for individual differences. Thus, reaction times increase as difficulty increases and decrease as order increases.

[0071] Vibrotactile taVNS improved working memory, consistent with previous findings from invasive and transcutaneous electrical vagus nerve stimulation. To investigate whether arousal regulation contributes to working memory improvement, skin conductance was used as an index of task engagement and arousal. Skin conductance was observed to increase before the N-back task, which may represent mental preparation for cognitive load. To examine the effect of vibrotactile VNS on the temporal dynamics of skin conductance, skin conductance for each N-back task was normalized from 0 to 1 and synchronized to the start of the task. The decrease in skin conductance was less rapid during the VNS session, indicating that vibrotactile VNS rescues the decline in task engagement due to sustained cognitive load. Temporal comparisons were performed to identify the time interval of interest. The difference in normalized skin conductance between the VNS and sham sessions was significant at the midpoint and end of the N-back task. The effect size (Cohen's d) exceeded 0.2 15 seconds after the start of the task, indicating a nontrivial effect size. Normalized skin conductance during the rest period between n-back tasks was similar across the three sessions. Furthermore, normalized skin conductance during each session was compared across three time intervals representing the early, middle, and late stages of the task. Normalized skin conductance during the VNS session was higher than that during the baseline and sham sessions during the mid-task phase (Cohen's d = 0.24 for VNS vs. sham sessions; Cohen's d = 0.25 for VNS vs. baseline sessions). During the late stage of the task, normalized skin conductance remained elevated during the VNS session (Cohen's d = 0.30 for VNS vs. sham sessions; Cohen's d = 0.16 for VNS vs. baseline sessions).

[0072] Skin conductance is thought to consist of two components: a phasic component reflecting sympathetic nervous system activity and a tonic component (i.e., skin conductance level) related to general arousal. To examine the effects of vibrotactile VNS on general arousal and task engagement during tasks of varying difficulty, skin conductance levels sampled every 10 seconds were z-scored for each session of the 1-back task to allow comparisons between subjects and sessions. We found that normalized skin conductance levels during the VNS session were higher when maximum working memory capacity was reached. Specifically, during the 3-back task, normalized skin conductance levels during the VNS session were significantly higher than those during the baseline session (permutation test, p = 0.02, Cohen's d = 0.22, Bonferroni-corrected p = 0.08). Normalized skin conductance levels were significantly higher in the VNS session during the 4-back task (permutation test, Bonferroni-corrected p = 0.03, Cohen's d = 0.23 for the VNS session vs. sham session comparison; Bonferroni-corrected p = 0.02, Cohen's d = 0.27 for the VNS session vs. baseline session comparison). These results indicate that vibrotactile VNS increases general arousal. To examine whether general arousal contributes to task performance, baseline-corrected performance measures d' were grouped based on skin conductance levels during the N-back task. For each N-back task of equal difficulty, the mean normalized skin conductance during the baseline session was subtracted from the mean normalized skin conductance during the VNS and sham sessions. The same procedure was performed for d'. The results indicated that there is an optimal skin conductance level for working memory task performance. Specifically, the baseline-corrected d' was significantly higher when the baseline-corrected skin conductance level was higher than the mean skin conductance level but lower than one standard deviation below the skin conductance level in the baseline session. Cohen's d for the baseline-corrected d' between baseline-corrected skin conductance levels of [-σ, 0] and [0, σ] was -0.49, with a Bonferroni-corrected p of 0.02.Furthermore, the effect size of the norm-corrected d' between the norm-corrected skin conductance levels of [0, σ] and [σ, 2σ] was 0.91, with a Bonferroni-corrected p of 0.02. These results indicate that there is an optimal level of arousal for better performance in working memory tasks. Furthermore, when the norm-corrected skin conductance level was within [0, σ], the mean hit rate was highest, the mean false alarm rate was lowest, and the mean reaction time was lowest compared to other skin conductance levels.

[0073] Animal studies have shown that pupil dilation reliably tracks VNS-induced basal forebrain cholinergic axon activity. It is hypothesized that the time-dependent decrease in pupil diameter would be rescued by vibrotactile taVNS. Preprocessed pupil diameter measurements contain two components: a 1.5 Hz oscillatory component representing the transient effects of on-screen stimulus size or luminance or vibrotactile taVNS, and a general trend representing general arousal. We observed that the left and right pupils showed similar changes. The mean absolute deviation was 0.19, the standard deviation was 0.11, and the mean Pearson correlation coefficient was 0.93, the standard deviation was 0.04. Therefore, the pupil diameter of the right pupil was selected as a measure of arousal.

[0074] Pupil diameter was z-scored to compare temporal dynamics between sessions. In addition to the periodic component due to digit presentation, a general trend of higher arousal was observed in the VNS session compared to the other sessions. A 0.1 Hz low-pass filter was used to reveal changes in general arousal. Arousal levels were found to rise to a high level after the onset of the task and then decline more slowly during the VNS session. This trend resembled the temporal dynamics of skin conductance. Temporal comparisons between the VNS and sham sessions using t-tests showed that pupil diameter after the onset of the task was larger in the VNS session. This difference peaked 10 seconds and 30 seconds after the onset of the task. The temporal dynamics of pupil diameter were further subdivided into three time intervals. The results of the permutation test indicate that the normalized pupil diameter during the VNS session was higher than that of other sessions in the [1 s, 10 s] interval (p = 0.01, Cohen's d = 0.35 for the comparison between the VNS session and the baseline session; p = 0.04, Cohen's d = 0.29, Figure 5d). To clarify the effect of vibrotactile taVNS during tasks of varying difficulty, the preprocessed pupil diameters were first interpolated and filtered with a 0.1 Hz low-pass filter. To examine how vibrotactile taVNS affects the relationship between pupil diameter and task difficulty, the average filtered pupil diameter during the one-back task was subtracted from the filtered pupil diameter for each session. Similar results were obtained for skin conductance, with corrected pupil diameter during the 4-back task being significantly higher in VNS sessions compared with sham sessions (permutation test, Bonferroni-corrected p<0.01, Cohen's d=0.25 for VNS vs. sham sessions; Bonferroni-corrected p<0.01, Cohen's d=0.32 for VNS vs. baseline sessions).

[0075] In another embodiment, the user computing device 125 receives a plurality of monitoring statistics for the subject from a past medical history. The user computing device 125 analyzes the plurality of monitoring statistics. The user computing device 125 determines one or more parameters of the nerve stimulation vibrotactile signal based on the analyzed monitoring statistics.

[0076] FIG. 4 illustrates an exemplary configuration of the client system shown in FIG. 1 , according to one embodiment of the present disclosure. User computing device 402 is operated by user 401. User computing device 402 includes, but is not limited to, VNS controller 105, vibration controller 110, and user computing device 125 (all shown in FIG. 1 ). User computing device 402 includes processor 405 for executing instructions. In some embodiments, executable instructions are stored in memory area 410. Processor 405 may include one or more processing units (e.g., a multi-core configuration, etc.). Memory area 410 is any device that allows for the storage and retrieval of information, such as executable instructions and / or transaction data. Memory area 410 may store one or more computer-readable media.

[0077] User computing device 402 also includes at least one media output device 415 for presenting information to user 401. Media output device 415 is any device capable of communicating information to user 401. In some embodiments, media output device 415 includes an output adapter (not shown), such as a video adapter and / or an audio adapter. The output adapter is operably coupled to processor 405. The output adapter is also operably coupled to output devices, such as a display device (e.g., a cathode ray tube (CRT), a liquid crystal display (LCD), a light-emitting diode (LED) display, or an "electronic ink" display) and an audio output device (e.g., speakers or headphones). In some embodiments, media output device 415 is configured to present a graphical user interface (e.g., a web browser and / or a client application) to user 401. The graphical user interface may include, for example, attributes of an object or attributes of a vibration stimulus. In some embodiments, user computing device 402 includes input device 420 for receiving input from user 401. User 401 can, for example, select to apply a vibration stimulus to a target using input device 420. Input device 420 can include, for example, a keyboard, a pointing device, a mouse, a stylus, a touch panel (e.g., a touchpad or touchscreen), a gyroscope, an accelerometer, a position detector, a biometric input device, and / or an audio input device. A single device, such as a touchscreen, can function as both media output device 415 and input device 420.

[0078] The user computing equipment 402 also includes a communication interface 425 that is communicatively coupled to a remote device, such as the VNS controller 105 or the user computing device 125. The communication interface 425 may include, for example, a wired or wireless network adapter and / or a wireless data transceiver for use in a mobile communications network.

[0079] Memory area 410 stores computer-readable instructions for, for example, providing a user interface to user 401 via media output device(s) 415 and, optionally, receiving and processing input from input device(s) 420. The user interface may include, among other things, a web browser and / or a client application. The web browser displays to a user (e.g., user 401) media and other information embedded in web pages or websites provided by a server and allows the user to interact with the user. The client application allows user 401 to interact with, for example, VNS controller 105. For example, instructions are stored in a cloud service and output of the execution of the instructions is sent to media output device(s) 415.

[0080] The methods and systems of the present disclosure can be implemented using computer programming or engineering techniques (including computer software, firmware, hardware, or any combination or subset thereof), and the technical effects can be achieved by performing at least one of the following steps:(a) stimulating the cutaneous distribution of the vagus nerve in the subject's ear with a nerve stimulation signal; (b) instructing the subject to perform an activity while the subject's vagus nerve is stimulated; (c) monitoring one or more statistical values ​​of the subject during the activity; (d) having the subject perform a mental activity while the subject's vagus nerve is stimulated; (e) assisting the subject in performing a physical activity; (f) measuring the subject's athletic performance; (g) adjusting one or more parameters of the nerve stimulation signal (electrical signal) to alter the subject's athletic performance; (h) controlling the subject's physical activity. (i) the subject's activity is assisted by a powered exoskeleton that assists and / or guides the subject's movement; (i) the subject's activity is assisted by a virtual reality headset; (j) the subject's activity is assisted by software visualization on a mobile computing device; (k) the subject has previously suffered a stroke; (l) the subject has previously suffered a spinal cord injury; (m) the subject has previously suffered a traumatic brain injury; (n) the subject has previously suffered multiple sclerosis; (n) the subject is neurologically normal and desires improved performance on a specific mental task. (o) the particular mental task is a learning task; (p) flash cards are presented to the subject as part of the activity; (q) the subject is neurologically normal and desires to improve motor performance of the particular task; (r) the particular task is a motor activity; (s) the particular task is a musical activity; (t) the particular task is a surgical activity; (u) the particular task involves a complex motor movement; (v) the stimulation is vibrotactile stimulation of the vagus nerve; (w) the stimulation is provided via a first form factor attached to the concha of the subject's ear; (x) a first form The factor is attached to the subject's left ear; (y) stimulation is provided to the auricular branch of the vagus nerve, which innervates the auricle; (z) receiving a plurality of subject attributes associated with the subject; (aa) analyzing the plurality of subject attributes; (bb) determining one or more parameters of a neurostimulation signal (electrical signal) based on the analyzed subject attributes; (cc) receiving a plurality of monitoring statistics of the subject from past treatment history; (dd) analyzing the plurality of monitoring statistics; and (ee) determining one or more parameters of a neurostimulation signal (electrical signal) based on the analyzed monitoring statistics.

[0081] In one embodiment, the computer program is embodied on a computer-readable medium. In one embodiment, the system executes on a single computer system without requiring connection to a server computer. In yet another embodiment, the system executes in a Windows® environment (Windows® is a registered trademark of Microsoft Corporation, Redmond, Washington, USA). In yet another embodiment, the system executes in a mainframe environment and a UNIX® server environment (UNIX® is a registered trademark of X / Open Company Limited, Reading, Berkshire, UK). In a further embodiment, the system executes in an iOS® environment (iOS® is a registered trademark of Cisco Systems, Inc., San Jose, California, USA). In yet another embodiment, the system executes in a MacOS® environment (MacOS® is a registered trademark of Apple Inc., Cupertino, California, USA). In yet another embodiment, the system runs in an Android® OS environment (Android® is a registered trademark of Google Inc., Mountain View, California, USA). In another embodiment, the system runs in a Linux® OS environment (Linux® is a registered trademark of Linus Torvalds, Boston, Massachusetts, USA). The application is designed to be flexible and able to run in a variety of environments without compromising its primary functionality. In some embodiments, the system includes multiple components distributed across multiple computing devices. One or more components may be in the form of computer-executable instructions embodied on a computer-readable medium. The systems and processes of the present disclosure are not limited to the specific embodiments described herein.Additionally, each system and process component may be implemented separately and independently from the other components and processes described herein. Each component and process may also be used in combination with other assembly packages and processes.

[0082] As used herein, the terms “processor” and “computer” and related terms, such as “processing device,” “computing device,” and “controller,” are not limited to integrated circuits commonly referred to in the art as computers, but broadly refer to microcontrollers, microcomputers, programmable logic controllers (PLCs), application-specific integrated circuits (ASICs), and other programmable circuits, and these terms are used interchangeably herein. In the embodiments described herein, memory includes computer-readable media such as, but not limited to, random access memory (RAM) and computer-readable non-volatile media such as flash memory. Alternatively, floppy disks, compact disk read-only memories (CD-ROMs), magneto-optical disks (MODs), and / or digital versatile disks (DVDs) may be used. Also, in the embodiments described herein, additional input devices may be computer peripherals associated with an operator interface, such as, but not limited to, a mouse and keyboard. Alternatively, other computer peripherals, such as, but not limited to, a scanner, may be used. Furthermore, in exemplary embodiments, additional output channels may include, but are not limited to, an operator interface monitor.

[0083] Furthermore, as used herein, the terms "software" and "firmware" are used interchangeably and include any computer program stored in memory that is executed by a personal computer, workstation, client, server, and their respective processing elements.

[0084] As used herein, the term "non-transitory computer-readable medium" is intended to refer to any tangible, non-transitory computer-based device implemented by any method or technology for short-term or long-term storage of information, such as computer-readable instructions, data structures, program modules or sub-modules, or other data stored on any device. Accordingly, the methods described herein may be encoded as executable instructions embodied by a tangible, non-transitory computer-readable medium (e.g., but not limited to, storage and memory devices). Such instructions, when executed by a processor, cause the processor to perform at least a portion of the methods described herein. Furthermore, as used herein, the term "non-transitory computer-readable medium" refers to any tangible computer-readable medium, such as, but not limited to, non-transitory computer storage devices. Such media include, but are not limited to, volatile or non-volatile media, removable or non-removable media (e.g., firmware, physical storage, virtual storage, CD-ROMs, DVDs, and other digital sources such as networks or the Internet), and yet-to-be-invented digital means, the sole exception being transitory propagating signals.

[0085] Furthermore, as used herein, the term "real-time" refers to at least one of the time of occurrence of relevant events, the time of measuring and collecting certain data, the time of a computing device (e.g., a processor) processing the data, and the response time of a system to events and circumstances. In the embodiments described herein, these activities and events are considered to occur substantially instantaneously.

[0086] The embodiments described herein may be implemented as part of one or more computer components, such as, for example, a client device, system, and / or components thereof. Additionally, one or more embodiments described herein may be implemented as part of a computer network architecture and / or cognitive computing architecture that facilitates communication between various other devices and / or components. Accordingly, the embodiments described herein address and solve technical problems that are inherently rooted in computer technology.

[0087] The processor or processing element may be trained using supervised or unsupervised machine learning. Machine learning programs may also use neural networks, such as convolutional neural networks, deep learning neural networks, reinforcement learning modules or programs, or hybrid learning modules or programs that train in two or more fields or areas of interest. Machine learning involves identifying and recognizing patterns in existing data to facilitate predictions for subsequent data. Models may be created based on example inputs to make valid and reliable predictions for new inputs.

[0088] Additionally or alternatively, machine learning programs may be trained by inputting sample data sets or specific data, such as images, object statistics, traffic timing, past trips, and / or actual timing, into the program. Machine learning programs may utilize deep learning algorithms that primarily focus on pattern recognition and may be trained after processing multiple examples. Machine learning programs may include Bayesian program learning (BPL), speech recognition and synthesis, image or object recognition, signal processing, optical character recognition, and / or natural language processing, individually or in combination. Machine learning programs may also include natural language processing, semantic analysis, automated reasoning, and / or machine learning.

[0089] Supervised and unsupervised machine learning techniques can be used. In supervised machine learning, a processing element can be provided with example inputs and their associated outputs and attempt to discover general rules that map the inputs to outputs, so that when subsequently provided with new inputs, the processing element can accurately predict the correct output based on the discovered rules. In unsupervised machine learning, the processing element must discover unique structures from unlabeled example inputs. In one embodiment, machine learning techniques can be used to determine the brain's response to stimuli, such as VNS settings.

[0090] Based on these analyses, the processing element can learn how to identify features and patterns that can be applied to the analysis of image data, model data, and / or other data. For example, the processing element can learn to identify brain responses to stimuli and VNS settings for various subjects to provide optimal gamma activity. The processing element can also learn how to identify trends that are not readily apparent based on collected traffic data, such as identifying when gamma activity spikes or drops.

[0091] Thus, the exemplary systems and methods described and illustrated herein provide a VNS process for improving the effectiveness of the learning process.

[0092] The computer-implemented methods and processes described herein may include additional, fewer, or alternative operational features, including those described elsewhere herein. The systems and methods of the present invention may be implemented using one or more local or remote processors, transceivers, and / or sensors (e.g., processors, transceivers, and / or sensors onboard vehicles, stations, nodes, or mobile devices, or those associated with smart infrastructure or remote servers), and / or with computer-executable instructions stored on a non-transitory computer-readable medium. Unless otherwise noted herein, various steps of some processes may be performed in different orders, or in some instances simultaneously.

[0093] In addition, the computer systems described herein may include additional, fewer, or alternative elements and functionality, including those described elsewhere herein, that include or are implemented according to computer-executable instructions stored on non-transitory computer-readable media.

[0094] In an exemplary embodiment, a processing element may be instructed to perform one or more of the above processes and sub-processes by providing the processing element with computer-executable instructions for performing the above steps / sub-steps, and the collected data (e.g., trust store, authentication information, etc.) may be stored in its associated memory or storage device. The stored information is used by each processing element to make decisions necessary to perform other associated processing steps, as described above.

[0095] The embodiments described herein may be implemented as part of one or more computer components, such as, for example, a client device, system, and / or components thereof. Additionally, one or more embodiments described herein may be implemented as part of a computer network architecture and / or cognitive computing architecture that facilitates communication between various other devices and / or components. Accordingly, the embodiments described herein address and solve technical problems that are inherently rooted in computer technology.

[0096] Although particular features of various embodiments of the present disclosure may be shown in some drawings and not in others, this is for convenience and in accordance with the principles of the present disclosure, any feature of one drawing may be referenced and / or claimed in combination with any feature of any other drawing.

[0097] Some embodiments involve the use of one or more electronic processing or computing devices. Such devices typically include a processor, processing unit, or controller, such as a general-purpose central processing unit (CPU), a graphics processing unit (GPU), a microcontroller, a reduced instruction set computer (RISC) processor, an application-specific integrated circuit (ASIC), a programmable logic circuit (PLC), a programmable logic unit (PLU), a field-programmable gate array (FPGA), a digital signal processing (DSP) device, and / or other circuitry or processing device capable of performing the functions described herein. The methods described herein may be encoded as executable instructions embodied by a computer-readable medium (such as, but not limited to, storage devices and memory devices). Such instructions, when executed by a processor, cause the processor to perform at least a portion of the methods described herein. The above examples are merely illustrative and thus are not intended to limit in any way the definition and / or meaning of processor and processing unit.

[0098] The computer-implemented methods described herein may include additional, fewer, or alternative operations, including those described elsewhere herein. The computer-implemented methods may be implemented via one or more local or remote processors, transceivers, servers, and / or sensors, or via computer-executable instructions stored on a non-transitory computer-readable medium.

[0099] In addition, the computer systems described herein may include additional, fewer, or alternative functionality, including those described elsewhere herein. The computer systems described herein may include or be implemented via computer-executable instructions stored on a non-transitory computer-readable medium.

[0100] This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and practicing any methods incorporated therein. The patentable scope of the invention is defined by the claims, and may include alternative embodiments that occur to those skilled in the art. Such alternative embodiments are within the scope of the claims if they include elements that do not deviate from the literal language of the claims, or if they include equivalent elements that do not deviate substantially from the literal language of the claims.

Claims

1. 1. A reinforcement learning method, comprising: stimulating a cutaneous distribution of the vagus nerve in the subject's ear with a nerve stimulation vibration signal; instructing the subject to perform an activity while the subject's vagus nerve is stimulated; and recording that the activity and the stimulation were performed simultaneously.

2. 10. The method of claim 1, The method, wherein the stimulation is vibrotactile stimulation to the vagus nerve at a frequency of 6 Hz.

3. 10. The method of claim 1, The method, wherein the stimulus is provided by a first form factor attached to the subject's concha.

4. 4. The method of claim 3, The method, wherein the first form factor is worn on the concha of the subject's left ear.

5. 4. The method of claim 3, The method, wherein the stimulation is provided to the auricular branch of the vagus nerve, which innervates the subject's pinna.

6. 10. The method of claim 1, The subject performs a mental activity while the subject's vagus nerve is stimulated.

7. 10. The method of claim 1, the subject performs a memory-based activity while the subject's vagus nerve is stimulated; The method further comprises assisting the subject in performing the memory-based activity.

8. 10. The method of claim 1, the subject performs a physical activity while the vagus nerve of the subject is stimulated; The method further comprises assisting the subject in performing the physical activity.

9. 9. The method of claim 8, measuring the subject's athletic performance; and adjusting one or more parameters of the neurostimulation signal to alter the exercise performance.

10. 10. The method of claim 1, The method, wherein the activity is assisted by a virtual reality headset.

11. 10. The method of claim 1, A method wherein the activity is supported by software visualization on a mobile computing device.

12. 10. The method of claim 1, The subject has previously suffered a stroke.

13. 10. The method of claim 1, The subject has previously suffered a spinal cord injury.

14. 10. The method of claim 1, The subject has previously suffered a traumatic brain injury.

15. 10. The method of claim 1, The subject has previously suffered from multiple sclerosis.

16. 10. The method of claim 1, The subject is neurologically normal and desires to improve performance on a specific mental task.

17. 17. The method of claim 16, The method wherein the specific mental task is a learning task.

18. 17. The method of claim 16, The method further comprising the step of displaying flash cards to the subject as part of the activity.

19. 10. The method of claim 1, The subject is neurologically normal and desires to improve motor performance of a particular task.

20. 20. The method of claim 19, The method, wherein the specific task is motor activity.

21. 20. The method of claim 19, The method, wherein the specific task is a musical activity.

22. 20. The method of claim 19, The method wherein the particular task is a surgical activity.

23. 20. The method of claim 19, The method, wherein the specific task involves a complex motor movement.

24. 10. The method of claim 1, receiving a plurality of object attributes associated with the object; analyzing the plurality of target attributes; determining one or more parameters of the neurostimulation signal based on the analyzed plurality of target attributes.

25. 10. The method of claim 1, receiving a plurality of monitoring statistics for the subject from a past medical history; analyzing the plurality of monitoring statistics; The method further includes determining one or more parameters of the neural stimulation signal based on the analyzed plurality of monitoring statistics.

26. 1. A system for reinforcement learning, comprising: a vibrotactile stimulator including at least one form factor; the vibrotactile stimulator is configured to provide vibrations that stimulate the vagus nerve of the subject via a vibrotactile signal during a subject activity; The vibrotactile signal is configured to stimulate a cutaneous distribution of a vagus nerve in the subject's ear with a nerve stimulation signal.

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