Auricular nerve stimulation devices, systems and related methods

Abstract

The present invention relates to a user-wearable auricular nerve stimulation device (1) configured to stimulate the auricular branch of the vagus nerve (ABVN) in a user's ear. The device (1) comprises at least two electrodes (2, 3) designed for placement within the auricle and the cavity of the concha, respectively. The electrodes (2, 3) stimulate the nerve branches of the auricle and the cavity of the concha, respectively, when a voltage difference is applied between them. The present invention also relates to an auricular nerve stimulation system including the described auricular nerve stimulation device (1) and a charging case (13) that allows the device (1) to charge its internal battery (10). The device (1) releases data captured by a photoplethysmography or biosensor (5) during stimulation to the charging case (13) and transmits these data to a dedicated platform on the cloud (15). The present invention also relates to a method of operating such an auricular nerve stimulation system.

Description

[Technical Field]

[0001] The present invention relates to a connected auricular nerve stimulator. The present invention further relates to an auricular nerve stimulation system including an auricular nerve stimulator, which has higher efficiency and can be personalized to each user and their needs. The present invention further relates to a method of operating such a system. [Background technology]

[0002] The vagus nerve (VN), the longest cranial nerve, is involved in regulating multiple systems and maintaining homeostasis. Cervical vagus nerve stimulation (VNS), a slow-acting treatment, was approved by the US Food and Drug Administration in 1997 for the management of treatment-resistant epilepsy and in 2005 for the management of chronic treatment-resistant depression. However, surgical risks and potential side effects limit its application. To overcome these barriers, several noninvasive transcutaneous vagus nerve stimulation (taVNS) techniques have been developed, which superficially stimulate the cervical VN in the neck or external ear.

[0003] The rationale for auricular taVNS is based on anatomical studies showing that certain regions of the ear have an afferent VN distribution. Electrical stimulation of the entire auricular branch of the vagus nerve (ABVN) and these regions can induce changes in activity in VN pathways in the brainstem and central structures, producing modulatory effects similar to those of invasive VNS.

[0004] The vagus nerve regulates metabolic homeostasis by controlling heart rate, gastrointestinal motility and secretion, pancreatic endocrine and exocrine secretion, hepatic glucose production, and other visceral functions. Furthermore, the vagus nerve is a key component of the neural reflex mechanisms that control innate immune responses and inflammation in response to pathogen invasion and tissue injury (the inflammatory reflex).

[0005] TaVNS is used to treat disorders such as epilepsy, pre-diabetes, depression, chronic retinal disorders, migraine, post-ischemic stroke rehabilitation, ventricular arrhythmias, and respiratory symptoms associated with COVID-19, and can also enhance associative memory, which has been proposed to assist patients with Alzheimer's disease and other dementia types. However, VNS has shown benefits beyond traditional therapeutic applications.

[0006] (Vagus nerve stimulation. Neuroanatomical network overview) The therapeutic mechanism of VNS (both invasive and taVNS) is thought to be via shifting concentrations of noradrenaline, gamma-aminobutyric acid (GABA), and acetylcholine (ACh) in the central nervous system, which induces neuroplastic changes in the cerebral cortex.

[0007] The solitary tract, or nucleus tractus solitarius (NTS), is the recipient of most afferent sensory fibers, but the vagus nerve also sends ipsilateral projections to the vomiting center, dorsal motor nucleus of the vagus nerve, nucleus ambiguus, medullary reticular formation, and spinal trigeminal nucleus. Because the NTS is an important processing and relay center for various important functions, it also integrates inputs from the glossopharyngeal nerve, facial nerve, trigeminal nerve, and numerous brain regions. The NTS also sends monosynaptic projections to diffuse brain regions, such as the face, trigeminal nerve, hypoglossal nucleus, dorsal motor nucleus of the vagus nerve, nucleus ambiguus, parabrachial nucleus, pons, respiratory system, and cardiovascular centers on the ventral surface of the medulla oblongata. Additionally, the brainstem monoamine nuclei, the locus coeruleus (LC) and raphe nuclei, receive direct and / or indirect projections from the NTS. Forebrain and limbic structures also receive NTS projections, including the bed nucleus of the stria terminalis, the paraventricular nucleus, the dorsal nucleus, and the arcuate hypothalamic nucleus, the preoptic area and periventricular hypothalamic nucleus, and the central amygdala. Even the cerebral cortex is affected after VNS, where an increase in GABA neurotransmitter concentrations is observed.

[0008] After stimulating the vagus nerve, the activity of numerous structures is hacked, resulting in numerous changes in body and brain function, some of which may improve physical and cognitive performance. These changes are numerous but can be categorized into four distinct groups: recovery, cognitive and motor skill enhancement, stress control, and weight and composition control.

[0009] (recovery) One of the beneficial mechanisms of exercise is that it reduces inflammation when performed regularly. Clinical studies have shown that consistent exercise reduces several inflammatory cytokines and, for this reason, can promote health. On the other hand, little or no exercise promotes increased inflammation. However, high levels of exercise can also promote high levels of inflammation, potentially affecting recovery. This balance between pro- and anti-inflammatory factors is crucial for elite athletes, for example.

[0010] Inflammation is usually a localized, temporary event, and after its resolution, immune and physiological homeostasis are restored. This response is particularly important for some sports. For example, weightlifters destroy muscles with some inflammation when they lift. They then rest to allow the muscles to regrow, and the regrowth becomes stronger and larger. Therefore, it is important to allow inflammation to normalize by resting for a few days after heavy lifting or by alternating the body parts being trained. Otherwise, further exercise and inflammation may not allow for this normal recovery and may eventually damage the muscles, and the inflammation may begin to cause problems throughout the body.

[0011] Acute inflammation strengthens, but chronic inflammation damages. This inflammation is seen in most, especially the most demanding sports and elite athletes. A study of triathletes reported significant increases in creatine kinase, C-reactive protein, aldosterone, and cortisol, along with decreases in testosterone and the testosterone:cortisol ratio. Another study evaluated these subjects' post-race parameters and found significant increases in total white blood cell count, myeloperoxidase, polymorphonuclear elastase, cortisol, creatine kinase activity, myoglobin, IL-6, IL-10, and high-sensitivity C-reactive protein, while testosterone significantly decreased compared to pre-race. Another study showed that intense exercise induces a systemic inflammatory response, which is associated with exercise-induced tissue / organ damage. In particular, activation of the master regulator nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is directly or indirectly involved in controlling pro-inflammatory gene and antioxidant enzyme expression, and nuclear factor-kappa B (NF-κB) regulates pro-inflammatory gene expression.

[0012] This inflammatory component lasts for a week or more, and only after this period can the athlete continue full training. However, this recovery period is too long for most elite athletes due to the type of sport (cyclists), the large number of games played during championship periods (baseball, soccer, basketball), or the need for athletes to train more frequently to improve their results. Therefore, strategic developments to shorten this recovery period would be very useful for these professional athletes, and VNS may play a role in shortening this time.

[0013] This chronic inflammatory state in athletes has been extensively studied in recent years. Proinflammatory cytokines, along with chemokines, reactive oxygen species, nitrogen intermediates, and other inflammatory molecules, are crucially involved in extracellular pathogen clearance, vasodilation, neutrophil recruitment, increased vascular permeability, and the induction of acute-phase proteins such as C-reactive protein and coagulation. This proinflammatory process is normally balanced by the release of IL-10, TGF-β, soluble cytokine receptors, and other anti-inflammatory molecules. However, when exercise is frequent and intense, as is typically the case in elite athletes, the proinflammatory cascade prevails, resulting in persistent systemic chronic inflammation, which may reflect incomplete muscle recovery.

[0014] This disrupted immune regulation can lead to persistent pro-inflammatory cytokines and excessive or chronic inflammation. This condition not only impedes recovery in professional athletes but may also be associated with a variety of disease syndromes, including sepsis, rheumatoid arthritis, inflammatory bowel disease, and other inflammatory and autoimmune disorders. The vagus nerve may help control the release of inflammatory cells and inflammatory cytokines when inflammation is no longer needed.

[0015] The body's adaptation to exercise is regulated by the sympathetic and parasympathetic (vagus) branches of the autonomic nervous system (ANS), typically measured by heart rate variability (HRV), or beat-to-beat fluctuations. Vagus nerve activity is typically stimulated after exercise, but in professional athletes, vagus nerve activity is impaired and autonomic regulation appears delayed after intense exercise. This is reflected in a decrease in heart rate. Meanwhile, early vascular recovery and post-exercise hypotension are still maintained. This suggests that professional athletes' autonomic nervous system regulation is impaired and the sympathetic branch of the ANS predominates, which may be associated with a long-term pro-inflammatory state and associated complications. Another study examined the time it takes for this sympathetic dominance to emerge in athletes, and specifically established that the shift to relative sympathetic dominance due to decreased vagal activity was evident after approximately eight years of competitive play at the professional level.

[0016] Some authors have established a relationship between this sympathetic dominance and several health problems frequently observed in athletes. Aubert et al. (2001) concluded that HRV is affected by chronic exercise, especially in endurance-trained athletes, and speculated that aerobic exercise in particular may have a beneficial effect on cardiovascular risk profiles. However, while regular exercise clearly reduces cardiovascular morbidity, long-term endurance sports practice has been recognized as a risk factor for atrial fibrillation (AF). Meanwhile, Cole et al. (1999) considered reduced vagal activity, assessed by a delayed decrease in heart rate during the first minute after graded exercise, as a strong predictor of overall mortality, independent of workload, and established a relationship between reduced vagal tone, the presence of impaired myocardial perfusion, and changes in heart rate during exercise.

[0017] VNS is a novel therapeutic approach with proven efficacy in treating inflammatory conditions and is believed to prevent chronic proinflammatory conditions in professional athletes. Indeed, VNS increases levels of the anti-inflammatory cytokine IL-10 and reduces other pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. In all professional soccer players, these specific pro-inflammatory cytokines, IL-6, IL-8, and TNF-α, were significantly elevated.

[0018] In recent years, an increasing number of studies have demonstrated that vagal activity is inversely related to chronic inflammation. These findings raise the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to the risk of inflammatory diseases, independent of demographic and health characteristics such as age, sex, race, years of education, smoking, hypertension, and white blood cell count. Vagus nerve stimulators implantable in patients with epilepsy have been demonstrated to suppress peripheral blood production of TNF-α.

[0019] Therapeutic VNS activates both efferent and afferent fibers of the vagus nerve. However, the effects of afferent stimulation of the vagus nerve are unclear. Although still debated, it appears to be via several pathways. The first pathway is the anti-inflammatory hypothalamic-pituitary-adrenal axis, which is stimulated by vagal afferent fibers and leads to a decrease in cortisol. The second pathway, called the cholinergic anti-inflammatory pathway, is mediated by vagal efferent fibers that synapse on enteric neurons, releasing acetylcholine (ACh) at synaptic junctions with macrophages. ACh binds to the α-7-nicotinic ACh receptor (α7nAChR) on these macrophages, inhibiting the release of TNF-α. The final pathway is the splenic sympathetic anti-inflammatory pathway, in which VNS stimulates the splenic sympathetic nerve. Norepinephrine (noradrenaline) released at the distal end of the splenic nerve links to β2-adrenergic receptors on splenic lymphocytes, which release ACh. Finally, ACh inhibits the release of TNF-α by splenic macrophages via α7-nicotinic ACh receptors. VN stimulation, as an invasive or non-invasive procedure, is gaining popularity, and several clinical trials are underway to evaluate the potential efficacy of this therapy in alleviating chronic inflammation. Indeed, this offers a new range of potential therapeutic approaches for controlling inflammatory responses.

[0020] (Improvement of cognitive and motor skills) Cognitive abilities and motor skills are important in everyone's daily life. Improving attention, concentration, memory, reaction time, or specific motor skills can provide a competitive advantage in some activities.

[0021] VNS has been associated with an increase in certain neurotrophins, particularly brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF), which may affect neurogenesis in the hippocampus of adult rats and increase memory. BDNF may play a role in protective mechanisms against brain injury and contributes to the development and maintenance of high levels of attention and concentration, particularly in combat sports. It is known that binding of BDNF to its receptor, TrkB, and VNS stimulates not only BDNF production but also its receptor, TrkB, increasing its effects.

[0022] VNS is known to increase norepinephrine (NE) in the brain. NE is thought to improve several aspects of cognitive control, including aiding focus and concentration by inhibiting irrelevant information. In certain sports, such as golf, baseball, basketball, soccer, and combat, inhibiting irrelevant information in decision-making is a fundamental skill. One study showed that VNS improved the ability to inhibit distracting interference and enhance cognitive control. Another study showed that VNS improved working memory performance and reduced errors on subtasks. Subtasks rely on working memory and increase reaction time in response to distractions. Recent research suggests that long-term VNS can be used to improve some learning processes, such as foreign language learning.

[0023] Indeed, long-term VNS can improve attention and concentration and avoid distractions not only in healthy subjects but also in some neurological disorders such as treatment-resistant depression. Application of VNS has shown sustained clinical and cognitive improvement in these patients, with several mental functions improving one month after the start of VNS therapy.

[0024] Creativity is one of the most important cognitive skills in our complex, rapidly changing world. Previous evidence has shown that GABA is involved in divergent thinking but not convergent thinking. Research results suggest that enhanced divergent thinking associated with creativity, compared with sham stimulation, is associated with active taVNS. One study suggested that GABA (likely due to taVNS) supports the ability to choose between competing options under high choice demands (divergent thinking), but not under low choice demands (convergent thinking), which may also be important for professional athletes. Another study showed that taVNS enhanced response selection processes, especially when choice demands were high.

[0025] However, VNS can improve not only cognitive abilities but also motor skills. Improved motor skills are associated with motor cortical plasticity. Indeed, this motor cortical plasticity is associated with the ability to acquire new skills and adaptations. Higher motor plasticity is thought to enhance motor learning.

[0026] VNS may help improve these motor skills by increasing plasticity in the motor cortex. Although there is no evidence that VNS can stimulate motor cortical plasticity and improve motor skills, there is considerable experience in improving motor plasticity in patients with brain injury. VNS combined with rehabilitation interventions improves motor recovery in chronic stroke. For these patients, noninvasive approaches such as taVNS are safe, well-tolerated, and can improve motor function in patients who are still debilitated. Another study showed that VNS combined with rehabilitation therapy improved motor outcomes in traumatic brain injury compared to a placebo group.

[0027] (Stress control) Psychological stress and recovery monitoring are important issues for health, well-being, and performance. People are frequently exposed to various situations and conditions that can cause chronic stress and interfere with normal performance. These stressful situations affect the activity of the autonomic nervous system and hormonal responses. In fact, a study by Lellamo et al. (2003) demonstrated a dissociation between the nervous and hypothalamic-pituitary-adrenal axis functions in response to competitive stress in elite athletes. A significant degree of competition may selectively alter the physiological function of stress-related hormones, suppress autonomic cardiac regulation, and affect productivity and performance.

[0028] Chronic stress is also associated with sleep deprivation. A study by Nedelec et al. (2015) demonstrated that sleep deprivation in elite soccer players negatively impacted the outcome of the post-match recovery process, resulting in impaired muscle glycogen replenishment, impaired repair of muscle damage, altered cognitive function, and increased mental fatigue. This is another reason to treat chronic stress, thereby improving recovery and performance.

[0029] Chronic stress is associated with decreased vagal tone, increased reaction time, and impaired decision-making. Some athletes work exhausting schedules and are under significant psychological pressure. This can decrease vagal tone, impair decision-making processes, increase reaction time, and ultimately impair physical and cognitive performance. Chronic vagal stimulation may reverse this decrease in vagal tone and, therefore, reverse these performance impairments.

[0030] This relationship between reduced vagal tone and chronic stress has also been described in other contexts. Zanstra, et al., (2006) studied differences in task performance and associated sympathovagal response patterns between burnouts and controls during a mentally demanding workday, and found that the burnout group exhibited a sympathetic dominance in the sympatho-vagal balance. Burnouts experienced increased effort and were more fatigued at the end of the workday.

[0031] TaVNS reduces sympathetic and enhances parasympathetic function, both in isolation and after stress exposure, helping to regulate autonomic tone. This can be used to reduce stress not only in elite athletes but also in a significant proportion of the current population. This regulation of autonomic tone can be assessed by spectral analysis of heart rate variability (HRV). This is a simple, noninvasive technique widely used to assess cardiac sympathetic versus vagal regulation. Its use is currently increasing, partly due to the increasing use of wearable devices. During chronic stress, the sympathetic nervous system becomes overactivated, leading to physical, psychological, and behavioral abnormalities. Current neurobiological evidence suggests that HRV is affected by stress, supporting its use as an objective assessment of psychological health and stress. Increased occupational stress has been found to be associated with decreased HRV, particularly parasympathetic activation. Several studies have used HRV to describe autonomic dysregulation, and these autonomic changes have been linked to performance levels. Measurement of HRV is often considered as a convenient non-invasive assessment tool for monitoring individual adaptations to training: decreases and increases in vagus-derived HRV indices indicate negative and positive adaptations, respectively, to endurance training regimens.

[0032] HRV can be used to measure athletes' adaptation to training loads without interrupting the training process. In recent years, an increasing number of studies have demonstrated that sympathetic nervous system dominance, considered a sign of physical or mental fatigue and chronic stress, is detrimental to athletes' performance, and VNS may reverse this abnormal dominance. In fact, maintaining high vagal activity during the preseason has also been associated with better outcomes. Because cardiac autonomic imbalance observed in overtrained athletes implies changes in HRV, heart rate variability may provide useful information for detecting overtraining in athletes and be a valuable adjunct tool for optimizing athletes' training programs. Meanwhile, early heart rate recovery (HRR) after exercise primarily depends on parasympathetic reactivation. Therefore, early accelerated HRR after exercise in endurance-trained athletes may be due to enhanced parasympathetic reactivation.

[0033] Other biomarkers associated with chronic stress were also altered by taVNS, indicating a role for taVNS in treating this chronic stress state. Salivary alpha-amylase and cortisol were altered using taVNS and compared to a sham control, supporting the use of taVNS to treat chronic stress.

[0034] (Weight and composition) Recently, the vagus nerve has been implicated in weight management and muscle preservation. The vagus nerve, which innervates the gut, plays a key role in metabolic control. It transmits peripheral information regarding the amount and type of nutrients between the gut and the brain. Depending on nutritional status, vagal afferent neurons express two distinct neurochemical phenotypes that can either inhibit or stimulate food intake. Long-term consumption of a calorie-rich diet reduces the sensitivity of vagal afferent neurons to peripheral signals and their constitutive expression to orexigenic receptors and neuropeptides. This disruption of vagal afferent signaling is sufficient to promote hyperphagia and obesity. Furthermore, vagal neuromodulation can be used to treat obesity. Although the mechanism is unclear, vagal nerve stimulation can prevent weight gain in response to a high-fat diet. Small clinical studies have demonstrated that vagal nerve stimulation promotes weight loss in patients with depression or epilepsy, and vagal dysfunction is associated with increased body mass index. In conclusion, there is strong evidence that the vagus nerve is involved in the development of obesity, demonstrating that it is an attractive target for treating obesity.

[0035] Other studies in animal models have highlighted the importance of the vagus nerve in influencing body weight. In pigs, VNS attenuated weight gain and backfat gain and reduced the ratio of waist fat depth to psoas muscle. In rats, VNS can regulate food intake in obese animals. These studies link neural stimulation to highly effective weight management. While the reasons for weight loss are unclear, VNS-induced reductions in body fat in rats may be due to the actions of both central and peripheral mediators. The VNS-associated reduction in food conversion efficiency may be mediated by downregulation of hypothalamic BDNF, endocannabinoid tone in mesenteric adipose tissue, and increased PPARα-dependent fatty acid oxidation in the liver, which could explain the associated behavioral effects of appetite suppression and increased energy expenditure.

[0036] However, the vagus nerve is involved not only in body weight but also in its composition, regulating the percentage of fat, another interesting parameter for athletes. Indeed, a sympathetic-vagal imbalance appears to be associated with sarcopenia in male patients. This idea suggests that VNS may be a therapeutic approach for patients with muscle wasting and increased peripheral sympathetic outflow. Compared to sham VNS, VNS significantly reduced cell apoptosis, necrosis, and inflammatory cell infiltration. VNS treatment also reduced inflammatory responses, attenuated oxidative stress, and improved vascular endothelial function.

[0037] Skeletal muscle produces and releases significant levels of IL-6 after prolonged exercise, making it a potential myokine. Muscle is also an important target for cytokines. IL-6 signaling has been implicated in stimulating hypertrophic muscle growth and myogenesis through regulation of muscle stem cell proliferation. Additional beneficial effects of IL-6 include regulating energy metabolism, which is related to the ability of actively contracting muscles to synthesize and release IL-6. Paradoxically, harmful effects of IL-6, such as promoting atrophy and muscle wasting, have also been proposed. Some inflammatory cytokines, such as IL-6, COX-2, and uPA, may play a role in inhibiting skeletal muscle growth induced by overtraining, a condition commonly observed in elite athletes, and this could be reversed by VNS.

[0038] Furthermore, muscle regeneration and growth are significantly slowed by the loss of IL-10. IL-10 plays a central role in regulating the switch of muscle macrophages from the M1 to M2 phenotype in injured muscle in vivo, and this conversion is necessary for normal muscle growth and regeneration. VNS has also been demonstrated to increase IL-10 levels, thus contributing to muscle regeneration and growth.

[0039] VNS is also associated with the release of several hormones related to muscle growth or loss. Testosterone secretion, on the other hand, is thought to be regulated by the vagus nerve. Animal studies have shown that rats with severed right vagus nerves showed a significant decrease in testosterone levels, and that various responses to testosterone are associated with different vagal responses. Therefore, although more research is needed, VNS may be useful in promoting muscle growth in athletes. VNS is also associated with the secretion of ghrelin, a hormone involved in multiple mechanisms, including cognition, learning, memory, sleep-wake cycles, taste, reward behavior, and glucose metabolism. This hormone is also involved in the secretion of growth hormone, a substance clearly related to muscle growth. However, the relationship between VNS and the balance between ghrelin and leptin is complex, and more research is needed. The relationship between VNS and IGF-I levels also needs to be evaluated. Because this hormone is an important factor in muscle growth, and only one study has examined the relationship between VNS and plasma IGF-I levels,

[0040] US2012 / 0035680(A1) and WO2019 / 014250(A1) describe a device that electrically stimulates the afferent fibers of the auricular branch of the vagus nerve, taking into account the user's pulmonary activity (Respiratory-Gated Vagal Afferent Nerve Stimulation - RAVANS). Stimulation control is performed using an electrical circuit connected to two electrodes that apply a stimulating voltage on one side and a respiratory belt equipped with a strain gauge on the other side. A nasal airflow detector (US2012 / 0035680(A1)) or a pulse sensor configured to measure blood pressure (WO2019 / 014250(A1)) transmits an electrical signal related to pulmonary activity. The need for the user to carry and connect multiple devices significantly reduces the device's ease of use.

[0041] The device incorporates two electrodes attached to the afferent fiber zone of the auricular branch of the vagus nerve, which are described as "small discs made of conductive material that are attached to the patient using adhesive bands. Similarly, pre-gelled circular or spherical silver / silver chloride electrodes can be used."

[0042] WO2019 / 005774(A1) describes a device for transcutaneous electrical stimulation of peripheral nerves, including the auricular branch of the vagus nerve. The device includes a control unit and a housing placed on or in the ear, with two electrodes connected to the control unit, which can adjust the current applied to the electrodes. The control unit or housing can be fitted with sensors for measuring physiological parameters of the user, and stimulation parameters can be adjusted based on the measurements. These parameters include heart rate variability (HRV) and oxygen saturation.

[0043] The document discloses a pair of electrodes positioned "on the outer periphery of a cylindrical interface member having a C-shaped cross section that engages a target portion of the patient's ear."

[0044] Therefore, the described device uses a standard-shaped housing for the electrode holder, which cannot guarantee a sufficiently good contact with the stimulated area due to the large anatomical differences in the human ear. Furthermore, the disclosed device uses a standard electrode shape, which also cannot guarantee a sufficiently wide and good quality contact due to the anatomical differences. Both of these characteristics reduce the effectiveness and comfort of the stimulation. Meanwhile, the document does not mention whether the stimulation is anodal or cathodal. It also does not mention adding a delay between the stimulation pulse and the return pulse.

[0045] EP 3100764 (A1) by Cerbomed describes a nerve stimulation device that uses two electrodes to stimulate only the nerve branches of the concha (cymba). However, these two electrodes are small because they must fit into the concha with sufficient space between them to avoid short circuits. On the other hand, they are placed on a standard support that has limitations in order to adapt to the variable shape of the user's concha. This often results in poor contact between the electrodes and the concha. Both characteristics result in a very small stimulation area in the concha, reducing the overall efficiency of the device. Furthermore, all of the device's electronics are external (outside the ear cavity). This makes the entire device very bulky and uncomfortable to use due to the significant required components, such as wiring and connections.

[0046] PCT / EP2015 / 001279 discloses a stimulation pattern for a nerve stimulator similar to that of EP3100764(A1): a trapezoidal asymmetric biphasic wave initiated by a positive pulse (anodal stimulation). The depolarization caused by anodal stimulation is estimated to be approximately one-seventh to one-third of the depolarization caused by cathodal stimulation (waveform initiated by a negative pulse). Summary of the Invention [Problem to be solved by the invention]

[0047] These known devices use electrical current as a means of stimulating nerve endings. However, anatomical studies conducted by the applicant have found that nerve endings in the auricle region correspond to mechanoreceptors and thermoreceptors, which respond to mechanical and thermal stimuli, respectively. Therefore, it is possible to activate these nerve endings with mechanical stimuli, such as fine touch or vibration, resulting in a more efficient device and easier application for the user. Furthermore, known devices stimulate nerves in areas of the ear where there is little or no concentration of ABVN, making the devices inefficient. Furthermore, personalization is important to properly adapt these devices to each user, which is not provided by state-of-the-art devices.

[0048] The object of the present invention is to provide a wearable, connected auricular nerve stimulation device that stimulates the nerve branches of the navicular and cavum conchae with greater efficiency, that is comfortable to wear, and that can be personalized to suit each user and their needs.

[0049] The present invention also aims at other objects and to solve other problems, as will appear elsewhere in this description. [Means for solving the problem]

[0050] In view of the aforementioned prior art, the object of the present invention is, according to a first aspect, an auricular nerve stimulation device configured as a wireless earphone or in the shape of an ear that can be worn by a user, configured to stimulate the auricular branch of the vagus nerve (ABVN) in the user's ear, comprising at least one electrode designed to be placed in the concha navicularis and another electrode placed in the concha cavity. The concha navicularis electrode utilizes the entire area of ​​the concha navicularis to stimulate the ABVN present in this zone when a voltage difference is applied to the concha navicularis electrode.

[0051] Preferably, the electrodes are made of biocompatible metals such as graphene, titanium, nickel titanium (nitinol), platinum, platinum iridium, non-toxic metals such as gold, conductive biocompatible inks for 3D printing, or flexible conductive biocompatible polymers that adapt to the anatomical structure of the stimulation zone, thereby offering excellent comfort and perfect fit to the patient's ear.

[0052] Typically, an auricular nerve stimulator further includes an earmold in which the electrodes are placed, the earmold being customized to the user's anatomy to achieve good contact between the electrodes and the stimulation zone.

[0053] Preferably, the auricular nerve stimulator of the present invention further includes a photoplethysmographic or biosensor that measures the amount of hemoglobin and oxyhemoglobin circulating in the superficial capillaries of the patient's or user's ear, data that is used to calculate heart rate, heart rate variability (HRV), and to detect the user's breathing phase (exhalation or inhalation).

[0054] The device of the present application can also detect the inspiratory / expiratory phase so that it can selectively stimulate during exhalation. This is done using photoplethysmography technology, which allows measurements to be made in the ear itself. Photoplethysmography technology, which allows measurements to be made in the ear itself, allows the stimulation circuitry, respiratory phase detection device (sensor), and controller to be integrated into the same circuitry that can be housed within the pinna.

[0055] Typically, the photoplethysmography or biosensor is configured to detect a low heart rate (bradycardia) in the user, in which case stimulation of the device is stopped to avoid cardiological risks.

[0056] Preferably, in the auricular nerve stimulator of the present invention, the stimulation performed thereby is synchronized with the expiratory-respiratory phase of the user.

[0057] Auricular nerve stimulators of the present invention typically implement three types of stimulation protocols: BEAT, BFS, and EVANS, all of which use variable stimulation parameters.

[0058] Preferably, the stimulation protocol is based on a waveform that is rectangular, biphasic, symmetrical, and has a delay between the negative and positive pulses.

[0059] In one preferred embodiment, the stimulation protocol is of the BEAT type, consisting of the successive application of bursts of pulses.

[0060] In another embodiment, the stimulation protocol is of the BFS (Breathing Focused on Stimulation) type, which combines periods of stimulation and rest, so that the user inhales during the rest periods and exhales during the stimulation. This type of protocol allows the user to focus their attention on the stimulation, which benefits from a meditative effect. It also extends the breathing period, which provides the added benefit of slow breathing. In this way, the BFS protocol has the additional beneficial effects of relaxation, meditation, and slow breathing.

[0061] In another embodiment, the stimulation protocol is of the EVANS (Exhalation Vagus Auricular Nerve Stimulation) type, in which stimulation is also synchronized with the user's exhalation, but does not require the user's attention because the stimulator detects the breathing cycle and stimulates only during exhalation. In this way, the stimulator is responsible for stimulating in synchronization with breathing, allowing the user to focus their attention on other activities.

[0062] Preferably, the charge applied to each user during each stimulation can be personalized. Initially, a charge is assigned to each user according to their profile, but the injected charge can be customized based on analysis of data captured by the biosensor. The stimulator can keep track of the applied charge by ceasing stimulation when a set charge for the session is reached. It is also possible to assign a daily maximum amount that the device will not exceed.

[0063] According to a second object, the present invention relates to an auricular nerve stimulation system including an auricular nerve stimulation device and a charging case in which the device can charge the built-in battery and to which the data captured by the photoplethysmography sensor during stimulation can be released and transmitted to a dedicated platform on the cloud.

[0064] Typically, the auricular nerve stimulation system of the present invention further includes a smartphone application that allows the user to interact with the nerve stimulation device.

[0065] The cloud-based platform can also integrate data obtained from devices for continuous monitoring of cardiac activity, such as watches, bracelets, or rings. Analysis of this data can, for example, reveal patterns of change in the user's stress and prescribe individualized stimulation therapy to prevent high peaks.

[0066] According to a third aspect, the present invention relates to a method of operating an auricular nerve stimulation system, comprising the steps of:

[0067] (before stimulation) a setting step for setting the amount of charge to be applied in each stimulation session and a maximum amount of charge per day for each user; defining a threshold for the perception and comfort of the stimulus by a user; selecting a stimulation protocol by a user; Includes:

[0068] (stimulus) When the device is placed in the user's ear, stimulation begins and continues until the allotted charge for the session is reached or the maximum charge for the day is reached. The stimulation can be therapeutic or non-therapeutic. During stimulation, the biosensor stores the user's measurements.

[0069] (after stimulation) Once stimulation is complete, the device downloads the session data to the charging case while the device's battery recharges. The charging case sends data from each stimulation session to the cloud so the information can be analyzed appropriately. The cloud platform stores the transmitted session data. An algorithm analyzes all the data to optimize the amount of charge needed for each user and can change it if necessary. Further algorithms can send notifications to the application for recommended stimulation sessions to prevent stress peaks based on data available on the platform in the cloud obtained from devices that continuously monitor cardiac activity.

[0070] Further features, advantages, and objects of the present invention will become apparent to those skilled in the art upon reading the following detailed description of non-limiting embodiments of the invention in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0071] [Figure 1] FIG. 1 is a detailed diagram of the various areas of the human ear that may be stimulated. [Figure 2] FIG. 1 is a perspective view of an auricular nerve stimulation device according to a first preferred embodiment of the present invention, illustrating its main components. [Figure 3] FIG. 3 is a side perspective view of the auricular nerve stimulation device according to the first preferred embodiment of the present invention shown in FIG. 2. [Figure 4] 3 is a perspective view of an auricular nerve stimulation device according to the first preferred embodiment of the present invention shown in FIG. 2, shown in position to be placed at a patient's ear. FIG. [Figure 5] 3 is a perspective view of the auricular nerve stimulation device according to the first preferred embodiment of the present invention shown in FIG. 2, viewed from its bottom position. FIG. [Figure 6] FIG. 1 is a schematic diagram of the components of a connected auricular nerve stimulation system of the present invention. [Figure 7] 3 is a perspective view of the auricular nerve stimulation device of the present invention in an alternative mode to the embodiment of FIG. 2, with electronics placed behind the ear. [Figure 8A] 1 is a graph showing a stimulation pattern of the auricular nerve stimulation device of the present invention. [Figure 8B]1 is a graph showing the stimulation pattern of an auricular nerve stimulation device of the present invention synchronized with the patient's exhalation. [Figure 9A] 1 is a first exemplary layout of a printed circuit board (PCB) of an auricular nerve stimulator of the present invention, where dashed lines represent flexible portions and solid lines represent rigid portions. [Figure 9B] FIG. 1 illustrates a second exemplary layout of a printed circuit board (PCB). [Figure 10] 1 is a graph showing vagal sensory evoked potentials (VSEPs) evoked by applied auricular stimulation comparing an auricular nerve stimulator of the present invention with a prior art stimulator. [Figure 11] FIG. 1 shows the landmarks that characterize the surface and length of the concha navicularis. DETAILED DESCRIPTION OF THE INVENTION

[0072] The subject of the present invention is a connected auricular nerve stimulator 1 that can be worn by the patient, as shown in Figure 1, which optimizes stimulation of the ABVN present in the concha navicularis and cavity of the concha.

[0073] According to a first preferred embodiment in which the device 1 is placed in the patient's ear, the auricular nerve stimulation device 1 of the present invention includes the following components, as shown in FIG.

[0074] Electrode 2 occupies the entire section of the concha navicularis (the only ear zone with 100% ABVN). In the preferred embodiment, this electrode is configured as the working electrode where cathodal stimulation is applied to maximize activation of the ABVN.

[0075] Electrode 3 placed in the concha cavity (ear zone at 45% ABVN). In the preferred embodiment, this electrode serves as the reference electrode for applying the voltage difference generated by cathodal stimulation.

[0076] Electrodes are typically made from biocompatible metals such as graphene, titanium, nickel-titanium (nitinol), platinum, platinum-iridium, non-toxic metals such as gold, conductive biocompatible inks for 3D printing, or flexible conductive biocompatible polymers that adapt to the anatomy of the stimulation zone, providing excellent comfort and perfect fit in the patient's ear.

[0077] Earmold 4: This component serves as support for the concha and cavum electrodes 2, 3, respectively, ensuring that the placement of the electrodes 2, 3 is appropriate to maximize stimulation of the concha and cavum. An advantage of this earmold 4 in the device 1 of the present invention is that it is custom-made to the user's anatomy and can therefore be individualized and shaped to optimally fit each patient's or user's anatomy. The earmold material is biocompatible and preferably thermoelastic, which improves its fit with the user's ear when the earmold is subjected to body heat.

[0078] Photoplethysmography or biosensor 5: This sensor measures the environmental temperature and the user's body temperature and serves to estimate the amount of hemoglobin and oxyhemoglobin circulating in the shallowest capillaries of the patient's or user's ear after the device 1 is placed on the patient or user. These data can be used to calculate biomedical variables such as heart rate, heart rate variability (HRV), oxygen saturation, and to detect the user's or patient's respiratory phase (exhalation or inhalation).

[0079] This photoplethysmography or biosensor 5 is capable of detecting a very low heart rate in the user, and if this is detected the device 1 is configured to automatically stop stimulation.

[0080] Furthermore, measurements made by the sensor allow for knowing how much charge needs to be applied to each user at any given time to achieve vagus nerve activation, allowing for the individualization of stimulation therapy and reaching a level of efficiency much higher than other existing devices known in the art.

[0081] Furthermore, the photoplethysmography or biosensor 5 can also detect the respiratory phase (exhalation or inhalation) of the patient or user wearing it in order to automatically synchronize the stimulation of the device 1 only with the user's exhalation so as to obtain more efficient activation of the vagus nerve.

[0082] Electronic circuit 6: The auricular nerve stimulation device 1 is equipped with an electronic circuit 6, which, as shown below, generating stimulation patterns with variable duration, intensity, burst and pulse frequency, number of pulses per burst, pulse width, pulse delay, etc., by applying a voltage difference between electrodes 2 and 3; generating a stimulation pattern synchronized with the user's exhalation; Control of the charge applied with each stimulus and the charge accumulated per day; exchanging data with external devices via a wireless connection; Data exchange with the charging case, Wireless charging of the battery 10 by electromagnetic induction using the charging case, The following functions can be realized.

[0083] Faceplate 12: The auricular nerve stimulation device 1 is equipped with a faceplate 12 that protects the electronic circuitry 6 and allows the user to easily lift the device to place and remove it from the user's ear or from the charging case 13.

[0084] Furthermore, as shown in FIG. 6, the external charging case 13 and the connection of the device 1 to an external cloud 15 of internal applications on a smartphone 14 constitute a complete auricular nerve stimulation system according to the present invention.

[0085] Charging case 13: When not in use, the auricular nerve stimulation device 1 is stored in a charging case 13 for wireless charging of the battery 10 by electromagnetic induction. When in use, the device 1 emits data captured by the photoplethysmography or biosensor 5 during stimulation to the case 13 and transmits them to a dedicated platform on an external cloud 15.

[0086] Smartphone application: The auricular nerve stimulator 1 has a smartphone application 14 that allows the patient or user to interact with the neurostimulator 1, for example to configure certain stimulation parameters. The application 14 exchanges data with a dedicated platform on the cloud 15 and sends to the dedicated platform on the cloud 15 data captured by the photoplethysmography or biosensor 5 during stimulation.

[0087] Stimulation Protocols: The auricular nerve stimulator 1 implements multiple charge-controlled stimulation protocols. Preferably, these are cathodal stimulation protocols. Charge is injected by applying a voltage difference across the concha electrode 2 relative to the concha electrode 3, which varies in real time depending on the electrode-to-skin contact impedance. The applied voltage difference is a rectangular, biphasic, symmetrical wave with a delay between the first and second pulses (see Figure 8A). The first pulse of the waveform, or stimulation pulse, is used to elicit the desired physiological effect, e.g., the initiation of an active potential in the nerve terminal, and the second pulse, or reversal pulse, is used to reverse the electrochemical process occurring during the stimulation pulse. The stimulation pulses are more negative (cathodal) than positive (anodal) pulses to achieve faster depolarization of the nerve terminal. It has been estimated that the depolarization produced by anodal stimulation is approximately one-seventh to one-third of that produced by cathodal stimulation (Daniel R. Merrill, et al., 2004). Therefore, cathodal stimulation requires less current to bring the nerve terminal to threshold. Adding a delay between the stimulation pulse and the reversal pulse also lowers the threshold and contributes to achieving an active potential in the nerve terminal. However, the delay should not be too long to prevent the products of the Faradaic reaction caused by the stimulation pulse from accumulating to a level that could cause tissue damage. A delay value of 0 to 150 μs is considered appropriate.

[0088] Stimulation protocols include pulse bursts, which improve the effectiveness of stimulation. Active potentials evoked in sensory auricular vagus nerve terminals in response to continuous stimulation, rather than a rhythmic sequence of these impulses, are unlikely to affect systemic regulation or brain activity. This is because graded, natural sensory information is encoded as a graded temporal density of non-graded impulses, which in turn is encoded as the instantaneous frequency of the impulses. On the other hand, the brain, with its vastly increased number of neurons and sophisticated processing, responds rationally to a series of impulses rather than a single or small number of impulses. Stimulation protocols can include bursts of 1 to 10 per second.

[0089] The current strength, pulse width, and pulse frequency are also variable in the stimulation protocol. Stimulation intensity can vary between 0 and 5 mA, as this range has been experimentally proven to be both comfortable for the user and sufficient to produce effective stimulation of nerve endings. Pulse width typically determines the type of fiber excited; short pulses recruit only easily excitable thick fibers, while long pulses recruit both thick and thin fibers. The ABVN is primarily composed of Aβ, Aδ, and C fibers (Safi, et al., 2016). Aβ fibers are 5–12 μm in diameter and are associated with sensitive functions. Aδ fibers are 3–6 μm in diameter and transmit localized pain, temperature, and touch. C fibers are 0.4–1.2 μm in diameter and transmit diffuse pain and temperature. Since it is desirable to stimulate Aβ fibers rather than Aδ or C fibers, stimulation pulses must be short. Values ​​of 50–250 μs have proven to be adequate. Another important parameter of stimulation is the frequency or number of pulses per second, since depending on the value, one type of fiber or another is activated. The frequency variation range of the stimulation protocol is 1–30 Hz.

[0090] The different stimulation protocols can be conceptually grouped into three modalities: BEAT-type protocols, where patient breathing is not taken into account, and BFS-type protocols that adapt to the user's breathing rhythm and establish guidelines; EVANS-type protocols, where the device automatically detects the user's inhalation and exhalation and stimulates only during exhalation; Includes:

[0091] BEAT-type protocols apply pulse bursts with variable parameters within the ranges mentioned above (see Figure 8A). BFS- and EVANS-type protocols also apply pulse bursts with variable parameters, but only during the user's exhalation (see Figure 8B). In BFS, the user synchronizes their exhalation with the moment of stimulation, while in EVANS, the device detects the exhalation and synchronizes the stimulation to it.

[0092] The auricular nerve stimulation device 1 of the present invention is configured to detect when a user exhales using photoplethysmography or a biosensor 5. The duration of a stimulation session depends on the charge (dose) assigned to the session and the stimulation intensity selected by the user. Initially, each user is assigned a charge according to their profile, but the applied charge can be customized based on analysis of data captured by the biosensor 5. The stimulation device tracks the applied charge by ceasing stimulation when the session's set charge is reached. It is also possible to assign a maximum daily dose and prevent the device from exceeding that maximum dose.

[0093] The auricular nerve stimulation device 1 of the present invention has been described in a preferred embodiment as shown in FIGS. 2 through 5. According to this embodiment, the electronic components of the device 1 are placed in the user's concha (ITE). However, a different possible embodiment of the device 1 of the present invention can be configured to be placed behind the ear (BTE), as shown in FIG. 7. The device components are similar to the preferred configuration (shown in FIGS. 2 through 5) but have a configuration that allows the device to be placed behind the user's ear. In this way, the electronic components of the device are placed behind the user's ear and are not visible externally. Furthermore, this BTE configuration is very comfortable for the user.

[0094] The electronic circuitry 6 of the device of the present invention is constructed on a printed circuit board (PCB) that combines rigid and flexible elements, as shown in Figures 9A and 9B. Figures 9A and 9B each show different example layouts. In both the in-the-ear (ITE) configuration of Figures 2-5 and the behind-the-ear (BTE) configuration of Figure 7, components can be stacked to form an assembly that can be inserted into faceplate 12. The electronic circuitry 6 includes the following elements: a central circuit 7 that controls all functions of the device, including communication with the smartphone and the charging case, generation of stimulation patterns, and adjustment of the voltage difference applied to electrodes 2 and 3 depending on the contact impedance between the skin and the electrodes; a voltage amplifier 8 which boosts the voltage supplied by the battery to the required level to provide the required voltage difference between electrodes 2 and 3 at any given time; a charging circuit 9 that utilizes the current generated in the coil 11; a battery 10 that can be charged by a current generated by a coil 11; a coil 11 that receives a magnetic field generated by a coil disposed in the charging case and generates a current to recharge the battery; Includes:

[0095] Figure 10 shows vagal sensory evoked potentials (VSEPs) evoked by auricular stimulation. (a) Stimulation was applied to the ear lobe, where no vagal nerve endings are present; (b) the electrode arrangement of the present invention, which has two large electrodes, one active electrode in the concha scapula and one counter electrode in the concha cavity; and (c) the electrode arrangement of the Cerbomed stimulator (corresponding to the prior art device disclosed in EP 3100764), which has two small electrodes in the concha scapula. Measuring VSEPs evoked by electrical ABVN stimulation with scalp EEG electrodes as far-field potentials has been demonstrated to be another method for assessing vagal responses (Fallgatter AJ, et al., 2003; Lewine JD, et al., 2019). The graphs were obtained by measuring neuronal electrical activity between points C3 and F3 of the International 10-20 EEG measurement system. Neural activity is generated by postsynaptic potentials generated in the nucleus of the solitary tract (NTS) in response to electrical stimulation of the ear (see FIG. 1B). The graph shown was obtained by averaging the neuronal responses (vagal sensory evoked potentials - VSEPs) after applying at least 50 electrical stimulation pulses. The amplitude of the VSEPs represents the effectiveness of the stimulation. Results obtained from measurements on 26 volunteers showed that stimulation performed as described in the present invention generated vagal evoked potentials with amplitudes 2.9 times greater than those generated by the Cerbomed stimulation device (prior art).

[0096] The auricular nerve stimulation device 1 of the present invention has several advantages over other nerve stimulation devices known in the art, particularly with regard to safety, effectiveness, comfort, usability, and personalization, as described below.

[0097] (safety) The photoplethysmography or biosensor 5 included in the stimulator 1 allows for the prediction of a very low heart rate and the cessation of stimulation to prevent a dangerous situation. Meanwhile, the circuit 6 tracks the daily charge introduced into the user and ensures that it does not exceed a limit. It also adjusts in real time the voltage difference applied to electrodes 2 and 3 depending on the contact impedance between the electrodes and the skin, preventing the applied current from rising to dangerous limits in the event of a sudden drop in impedance, for example due to effects such as electroporation.

[0098] (Effectiveness) A study using vagal sensory evoked potentials (VAEP) showed that stimulation with one electrode (electrode 2) covering the entire concha scapha and another electrode (electrode 3) placed within the concha cavity produced a 3.9-fold greater neuronal response associated with vagal activation than stimulation with two electrodes placed within the concha. One reason for this is that the two electrodes within the concha scapha (100% vagal nerve fibers) require a minimum distance between them, which means that the entire surface of the concha is not fully utilized.

[0099] In general, the surface of the concha, like the entire ear anatomy, is highly variable. In an anthropometric study conducted on 326 volunteers (Wonsup Lee, et al., 2018), the lengths (see Figure 11) between the superior concha and the anterior concha (SC-AC) and between the posterior concha and the anterior concha (PC-AC) were measured.

[0100] [Table 1]

[0101] In terms of gender differences, the average lengths of the SC-AC and PC-AC were longer in men than in women, with the SC-AC being 18% longer and the PC-AC being 7% longer.

[0102] The auricular nerve stimulation device 1 of the present invention is designed to maximize stimulation in the concha navicularis. When the term "large-surface electrode covering substantially the entire surface of the concha navicularis" is used herein, it refers to an electrode 2 that occupies 75% or more of the concha navicularis surface. Therefore, taking into account human anthropometric standards and the values ​​shown in the table above, depending on variables such as the user's age, gender, and size, the electrode 2 may be 25 mm or larger. 2 ~45mm 2 The surface area of ​​the substrate may be 1000 nm or less.

[0103] Electrode 3 is placed in the cavity of the concha, which contains 45% of the vagus nerve endings and is also stimulated.

[0104] Both electrodes 2 and 3 are placed in an earmold 4. The earmold 4 is customised to the user's anatomy to ensure the best possible contact quality between the electrodes and the area to be stimulated.

[0105] On the other hand, according to Merrill et al. (2005), cathodal stimulation (where the stimulation pulse is negative) is 3 to 7 times more effective than anodal stimulation, and furthermore, adding a delay between the stimulation pulse and the reversal pulse reduces tissue damage and improves the effectiveness of the stimulation.

[0106] The auricular nerve stimulation device 1 of the present invention provides a cathodal stimulation pattern of the electrode 2 (the concha) and a delay between the stimulation pulse and the reversal pulse (see image 8A).

[0107] Additionally, the device 1 can implement BFS or EVANS protocols in which stimulation is synchronized with the user's exhalation, thereby promoting parasympathetic activation. During exhalation, activation of arterial baroreceptors triggers excitation of second-order neurons in the nucleus tractus solitarius (NTS), which increases the firing rate of cardiovascular neurons in the premotor cortex. Furthermore, during inspiration, the NTS receives inhibitory input from the ventral respiratory nucleus of the medulla oblongata, reducing vagal outflow to the heart, which can lead to respiratory sinus arrhythmia (RSA). Because the dorsal medullary vagal system functions in coordination with respiration, gating vagal afferent stimulation to the expiratory phase of respiration can optimize ABVN stimulation and its effects on cardiac vagal regulation.

[0108] (Comfort) If the current density (amount of current per unit area) is too high, transcutaneous electrical stimulation can cause a throbbing sensation. A way to avoid this unpleasant sensation is to distribute the current evenly over a large contact area. To achieve this, the device 1 of the present invention uses large-surface electrodes, which are placed on the earmold 4 and have a shape customized for each user. In this way, the contact zone between the electrode and the stimulation zone is large and of good quality, allowing the current to flow without being excessively concentrated at any point.

[0109] (usefulness) Most auricular nerve stimulation devices known in the art consist of a large generator connected by a cable to an accessory that applies a voltage difference to a part of the ear. The volume and weight of the set limit its portability and availability. However, the auricular nerve stimulation device 1 of the present invention has been developed as a small, lightweight device that can be worn comfortably. Furthermore, because it is configured as a wireless earphone or ear-shaped device, it is very simple to use, as users will recognize it as a familiar product. In this regard, it is also important to emphasize the technical feature that the miniaturized faceplate (12) incorporates all elements of the electronic circuit (6) configured on a printed circuit board (PCB) that can be wirelessly connected to other devices or systems.

[0110] (Individualization) The auricular nerve stimulation device 1 of the present invention includes two types of customization: anatomical and therapeutic, as described below. Anatomical customization consists of customizing the shape that contacts the user's ear. To achieve this, a sample can be taken from the user's ear and scanned. Another option is to directly 3D scan the user's ear. The 3D geometry generated in both options is used to create a custom earmold 4. A faceplate 12 is added to the custom earmold 4 along with electronic circuitry 6, and the stimulation device 1 is then manufactured. Therapeutic customization consists of the individualization of the charge (dose) introduced by the stimulation and the possibility of stimulating in synchronization with the user's breathing (EVANS / BFS protocol).

[0111] Furthermore, when integrating data from devices for continuous monitoring of the user's cardiac activity, such as watches, bracelets, rings, etc., analysis of this data can, for example, identify patterns of changes in the user's stress and prescribe individual stimulation therapy to prevent high peaks.

[0112] The auricular nerve stimulation device 1 of the present invention is a connected device, and its connection is via two paths: on the one hand, it can be wirelessly connected (e.g., via Bluetooth®) to an application for a smartphone, which in turn is connected to software on the cloud; and on the other hand, the charging case 13 is connected to the software on the cloud in order to be able to transmit usage data of the stimulation device, including data captured by the photoplethysmography or biosensor 5.

[0113] In a broader way, as mentioned above, the present invention further relates to an auricular nerve stimulation system comprising the described auricular nerve stimulation device 1, an external charging case 13 and a connection for correct connection and parameterization of the internal application in the device to software on the cloud.

[0114] The method of operation of the auricular nerve stimulation system according to the present invention includes several steps, which are described in detail below.

[0115] (before stimulation) 1. The user creates an account on the system using a smartphone or web application. To register, the user is asked to provide a set of personal data. 2. The system assigns an initial charge value (therapeutic dose or reference value for non-therapeutic use) and a maximum daily charge to apply to each stimulation session depending on the user's profile. The initial stimulation charge and maximum daily charge are assigned based on statistical studies. However, analysis of data captured by photoplethysmography or biosensors 5 when the stimulation device is used allows these values ​​to be customized. 3. Once registration is complete, the user logs into the application, connects to Device 1, and matches the serial number to the user account, which associates Device 1 with the user. 4. The application asks the user to set a "perception and pain threshold" (this can be changed at a later stage). The pain threshold indicates that Aβ type fibers have been stimulated and that Aδ and C type fibers are beginning to be stimulated. Using the values ​​of both thresholds, the application establishes the required range within which to place the stimulation intensity so that the stimulation is both effective and comfortable. In this way, the user can select the most comfortable stimulation intensity within the range set by the application. This intensity value can be changed whenever the user wishes, but will always be within the range established by the application. 5. The user selects a stimulation protocol from the available protocols (BEAT, BFS, or EVANS type). The application sends the data of the selected protocol to the device 1. From now on, the stimulation device can operate autonomously without connecting to a smartphone. Connecting to a smartphone is only necessary if the user wants to change the stimulation protocol or stimulation intensity.

[0116] (stimulus) 1. When the user removes the device 1 from the charging case 13, the device is detected and activated by a magnetic switch connected to the case 13. The proximity detector of the photoplethysmography or biosensor 5 also detects that the device is in the ear. When the stimulation device is properly positioned in the user's ear and there is good contact impedance between the electrodes and the stimulation zone, the device 1 automatically begins stimulation according to the defined stimulation conditions. Stimulation can be therapeutic or non-therapeutic. 2. Device 1 tracks the charge being applied to the user's ear and automatically stops when an assigned value (therapeutic dose or reference value for non-therapeutic use) is reached, or when a daily limit is reached or the user removes the device (detected by photoplethysmography or proximity detector in sensor 5). 3. During stimulation, the photoplethysmography or biosensor 5 stores measurements of the user's temperature, hemoglobin, and oxyhemoglobin.

[0117] (after stimulation) 1. Once stimulation is complete, the device 1 downloads the session data (date, time, stimulation duration, stimulation parameters, and biosensor data) to the charging case 13 or smartphone application 14 to prepare for the next session. Additionally, the battery 10 of the device 1 is wirelessly recharged in the case 13. 2. The charging case 13 or smartphone application 14 transmits the data from each stimulation session to the cloud, so that the information can be appropriately analyzed. 3. The cloud platform stores the transmitted session data. 4. The algorithm analyzes all the data and optimizes the amount of charge required for each user. If a change is determined, the platform sends the new values ​​to the application, which then uses these newly changed values ​​for the next stimulation. 5. If the user has data available on the platform in the cloud, obtained from a device for continuous monitoring of cardiac activity, e.g. a watch, bracelet, ring, etc., further algorithms can send notifications to the application for recommended stimulation sessions to prevent stress peaks.

[0118] Although the present invention has been described with reference to preferred embodiments thereof, many modifications and variations can be made by those skilled in the art without departing from the scope of the invention as defined by the appended claims.

Claims

1. 1. An auricular nerve stimulation device (1) configured to stimulate the auricular branch of the vagus nerve (ABVN) in a user's ear and wearable by a user, comprising: The auricular nerve stimulation device (1) comprises at least two electrodes (2, 3) designed to be placed in the concha navicularis and the cavity of the concha, respectively; The electrodes (2, 3) electrically stimulate the nerve branch in the concha navicularis and the nerve branch in the concha cavity, respectively; The auricular nerve stimulation device (1) is configured as a wireless earphone having an earmold (4) and a miniaturized faceplate (12), The electrodes (2, 3) are arranged on the earmold (4), the earmold (4) is customized to fit the anatomical structure of the user's ear so that the electrode placed on the concha is a large-area electrode that covers substantially the entire surface of the concha of the user's ear; a photoplethysmography or biosensor (5) having a miniaturized configuration is placed in the earmold (4); The miniaturized faceplate (12) incorporates all elements of an electronic circuit (6) therein, in an in-the-ear (ITE) or behind-the-ear (BTE) configuration, the electronic circuit (6) being constructed on a printed circuit board (PCB) that combines rigid and flexible elements and consisting of stacked components to form an assembly that can be inserted into the miniaturized faceplate (12). Auricular nerve stimulator (1).

2. the electrodes (2, 3) are made of graphene, biocompatible metals, non-toxic metals, conductive biocompatible inks for 3D printing, or flexible conductive biocompatible polymers; The earmold (4) is made of a biocompatible material. An auricular nerve stimulation device (1) according to claim 1.

3. the biocompatible material of which the earmold (4) is made is thermoelastic, thereby improving the fit with the user's ear when the earmold is subjected to body heat; Auricular nerve stimulation device (1) according to claim 2.

4. the photoplethysmograph or biosensor (5) measures the ambient temperature and the user's body temperature and estimates the amount of hemoglobin and oxyhemoglobin circulating in the shallowest capillaries of the user's ear, and the measurements made by the photoplethysmograph or biosensor (5) are used to calculate heart rate, heart rate variability (HRV) and oxygen saturation, and to detect the user's respiratory phase (exhalation or inhalation); The measurements made by the photoplethysmography or biosensor (5) are used to determine the optimal charge for the user at any given time. An auricular nerve stimulation device (1) according to claim 1.

5. The electronic circuit (6) a central circuit (7) that controls all functions of the auricular nerve stimulation device (1); a voltage amplifier (8) for boosting the voltage supplied by the battery (10); a charging circuit (9) utilizing a current generated in a coil (11) receiving a magnetic field generated by another coil placed in a charging case (13); a battery (10) that can be recharged with the current generated by the coil (11); Equipped with An auricular nerve stimulation device (1) according to claim 1.

6. The electronic circuit (6) generating stimulation patterns with variable duration, intensity, burst and pulse frequency, number of pulses per burst, pulse width, and pulse delay defined by the time interval between two adjacent pulses; generating a stimulation pattern synchronized with the user's exhalation; Control of the charge applied with each stimulus and the charge accumulated per day; exchanging data with external devices via a wireless connection; data exchange with the charging case (13); Wireless charging of the battery 10 by electromagnetic induction using the charging case (13); configured to: An auricular nerve stimulation device (1) according to any one of claims 1 to 5.

7. the stimulation provided by the electrodes (2, 3) is synchronized with the user's exhalation; An auricular nerve stimulation device (1) according to any one of claims 1 to 6.

8. the electronic circuit (6) implements a plurality of stimulation protocols; The current intensity, pulse width, and pulse repetition frequency are variable; the stimulation protocol is based on a rectangular, biphasic, symmetric waveform with a delay between the negative and positive pulses; An auricular nerve stimulation device (1) according to any one of claims 1 to 7.

9. The stimulation protocol comprises: a BEAT type protocol consisting of the successive application of bursts of pulses; a BFS (Breathing Focused on Stimulation) type protocol that combines a stimulation period and a rest period, in which the user inhales during the rest period and exhales during the stimulation period; an EVANS (Exhalation Vagus Auricular Nerve Stimulation) type protocol that stimulates only during the user's exhalation; Contains any of the following: Auricular nerve stimulation device (1) according to claim 8.

10. the amount of charge applied to the electrodes (2, 3) is personalized for the user; An auricular nerve stimulation device (1) according to any one of claims 1 to 9.

11. The voltage difference applied to the electrode placed in the concha cavity relative to the electrode placed in the concha navicularis is adjusted in real time according to the contact impedance between the electrodes and the skin so that the intensity of the stimulation is established. An auricular nerve stimulation device (1) according to any one of claims 1 to 10.

12. The auricular nerve stimulation device (1) is stored in a charging case (13) when not in use for wirelessly charging the battery (10) by electromagnetic induction; The auricular nerve stimulation device (1) releases data captured by the photoplethysmography or biosensor (5) during stimulation to the charging case (13) and transmits it to a dedicated platform on the cloud (15). An auricular nerve stimulation device (1) according to any one of claims 1 to 11.

13. An auricular nerve stimulation system comprising the auricular nerve stimulation device (1) according to any one of claims 1 to 12, The auricular nerve stimulation device (1) can be configured by a smartphone application. Auricular nerve stimulation system.

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