Device and system for adjusting arterial blood pressure of user

Abstract

To provide a device for adjusting arterial blood pressure of a user.SOLUTION: A device for adjusting arterial blood pressure of a user includes a signal generator for generating an electric stimulus signal, a controller connected to the signal generator to determine the form of the electric stimulus signal, and an earpiece connected to the signal generator and the controller to include electrodes. The earpiece includes a stimulating electrode for giving the electric stimulus signal to nerves that stimulate an earlobe of the user and a reference electrode. In the earpiece, the stimulating electrode is arranged in contact with a first surface of the earlobe and the reference electrode is arranged in contact with a second surface of the earlobe opposite from the first surface when attached to the earlobe. The controller is configured so as to transmit the electric stimulating signal to the stimulating electrode. The electrodes are attached in contact with the earlobe of the user. The electric simulating signal includes continuous electric pulses. Each electric pulse repeats at frequencies equal to or more than 1 Hz and equal to or less than 100 Hz, and has a duration of 10 to 500 microseconds and an intensity of 0.1 to 8 mA.SELECTED DRAWING: Figure 1B

Description

Technical Field

[0001] The present invention relates to a non-invasive neuromodulation device and method for adjusting and improving blood flow in the brain (also referred to as cerebral blood flow in this specification). This technique is based on applying specially programmed electrical stimulation signals to the cranial nerve cutaneous projections. Thereby, the arterial blood pressure and left ventricular hypertrophy of hypertensive subjects are substantially reduced, or the cardiac function of heart failure subjects is improved. The present invention can also be applied to users aiming at reducing systemic arterial blood pressure, reducing left ventricular hypertrophy, reducing pulmonary arterial blood pressure, treating heart failure or atrial fibrillation.

Background Art

[0002] Systemic arterial hypertension (commonly also referred to as "hypertension", "essential hypertension" or "hypertensive disease") is a state in which the systemic arterial blood pressure is chronically high.

[0003] Left ventricular hypertrophy (LVH) is a state in which the myocardial mass is increased. This is caused by an increase in wall thickness or left ventricular volume or both. Hypertension is the most common cause of LVH.

[0004] Pulmonary arterial hypertension is a state in which the blood pressure in the pulmonary artery is chronically high.

[0005] Heart failure (also referred to as "congestive heart failure", "congestive heart failure" or "chronic heart failure") is a state in which the heart cannot perform a sufficient pumping function to maintain an appropriate blood flow in the organs or tissues as required by the body.

[0006] Atrial fibrillation (also called AF) is a symptom in which an arrhythmia characterized by rapid and irregular beating of the atria is observed in a patient.

[0007] Worldwide, hypertension is a major risk factor for health. Hypertension is associated with cardiovascular adverse events that increase the risks of myocardial infarction, heart failure, aneurysm, renal failure, and stroke. The management of hypertension is very important. For every 10 mmHg reduction in blood pressure, coronary artery disease decreases by 17%, stroke decreases by 27%, heart failure decreases by 28%, and mortality from all causes decreases by 13%. The guidelines of the American Heart Association define hypertension as a systolic blood pressure of 130 mmHg or higher or a diastolic blood pressure of 80 mmHg or higher. Applying this guideline, in the age group of 45 to 75 years, 70.1 million people in the United States and 15 million people in the United Kingdom would have hypertension. This exceeds 60% of the total population in this age group (J Am Coll Cardiol 71:e127, 2018). In Europe, only one-third of patients with hypertension are being diagnosed and treated to achieve the recommended level of arterial blood pressure (Circulation 2016;134:441-450). If hypertension is the second condition after another symptom, it is generally wise to treat the first symptom first. There are various pharmaceutical treatment methods for hypertension. However, pharmaceutical treatment is often not sufficiently effective. Approximately 15% of all patients with hypertension have drug resistance (Hypertension. 2018;72:e53-e90), and most require more than two drugs. The efficacy is as low as approximately 50% of all patients. Many patients require more than two drugs for blood pressure management, but more than 90% of such patients do not comply and fail to achieve the recommended level of blood pressure control. The potential reasons include difficulties in accessing treatment, inappropriate dosing or combinations, patients' lack of enthusiasm for treatment, co-administration with other interacting drugs, or treatment-resistant hypertension. There are also not a few patients with hypertension who are negative about pharmaceutical treatment. This is because some antihypertensive drugs can disrupt patients' daily lives or cause side effects, and there are also patients who prefer alternative drugs for other reasons (BMJ 2012;345:e3953.).

[0008] Left ventricular hypertrophy (LVH) exists in 15% to 20% of the total population. In the case of the elderly, obesity, and hypertension, the prevalence further increases. Two out of three LVH patients have hypertension. According to the analysis results of 37,700 echocardiogram data, the prevalence of untreated hypertensive patients is 19 - 48%, and that of high-risk hypertensive patients is 58 - 77% (J Hum Hypertens 26: 343 - 349, 2012). Although LVH is compensatory hypertrophy, ultimately, it is an abnormal increase in left ventricular myocardial weight caused by chronic overload of the myocardium. The diagnosis of LVH is based on the evaluation of left ventricular weight. Echocardiogram is one of the options for examination methods in the diagnosis of LVH.

[0009] Echocardiogram utilizes the transthoracic or transesophageal placement of the transducer to measure the end-diastolic diameter of the left ventricle, the thickness of the posterior wall, and the thickness of the ventricular septum. From these measured values as well as the patient's height and weight, the left ventricular myocardial mass index can be calculated. The treatment of LVH must be aggressive. This is because LVH patients have the highest risks of cardiovascular diseases and death. The purpose of treatment is to reduce LVH and prevent left ventricular failure and heart failure. Antihypertensive therapy is beneficial to patients in that it can lower arterial blood pressure, reduce the degree of LVH independently of blood pressure reduction, and thereby reduce the morbidity and mortality of cardiovascular diseases (Eur Heart J 39: 3021 - 3104, 2018).

[0010] Pulmonary hypertension includes a group of serious clinical concepts such as pulmonary arterial hypertension (PAH). In PAH, progressive loss or obstructive remodeling of the pulmonary vascular bed causes an increase in pulmonary artery blood pressure and pulmonary vascular resistance. This leads to progressive right heart failure and reduced right heart function. Pulmonary arterial hypertension is classified into five groups according to its causes. Group 1: Idiopathic PAH of unknown cause Group 2: Pulmonary hypertension due to left heart disease Group 3: Pulmonary hypertension due to lung disease Group 4: Pulmonary hypertension due to chronic coagulation Group 5: Pulmonary hypertension with other symptoms Current PAH treatments cannot identify targeted pulmonary vascular remodeling or inflammation. Therefore, in order to support therapeutic innovations aimed at reversing symptoms such as progressive pulmonary artery lumen stenosis, perivascular inflammation, and vessel loss, and regenerating normal pulmonary blood vessels, it has become an urgent issue to more precisely identify the pathological mechanisms underlying these symptoms (Eur Respir J 53: 1801887, 2019).

[0011] Chronic heart failure (CHF) is one of the most common causes of disease and death in developed countries. Heart failure is associated with a wide range of complications, including lethal arrhythmias and death due to disease progression. Furthermore, CHF can be the end state of many cardiovascular diseases, including hypertension, myocardial infarction (MI), valvular heart disease, and various cardiomyopathies. The diagnosis of CHF is based on the assessment of the left ventricular ejection fraction (LVEF) of the heart. Heart diseases with normal LVEF (≧50%) are defined as heart failure with preserved ejection fraction (HFpEF). On the other hand, CHF with low LVEF (<40%) is defined as heart failure with reduced ejection fraction (HFrEF). The goal of heart disease treatment is to improve the patient's clinical status, functional ability, and quality of life, and reduce hospitalization and mortality rates. Established pharmacological treatments for HFrEF include several drug classes, including beta-adrenergic receptor blockers (β-blockers), diuretics, and renin-angiotensin-aldosterone system inhibitors, which improve symptoms and reduce mortality. However, drug treatment remains insufficient because cardiac function declines over time and the prognosis of most patients is poor. Furthermore, there is currently no treatment for HFpEF, which has become an urgent clinical issue to be solved.

[0012] Atrial fibrillation (AF) is a symptom observed in patients where an arrhythmia characterized by rapid and irregular beating of the atria (also called episodes) occurs. This starts as short-term irregular beating, but as the disease progresses, it becomes longer-term or persistent. It may also start as another form of arrhythmia (such as atrial flutter) that progresses to AF. Often, the arrhythmia of AF is asymptomatic. Sometimes, symptoms such as palpitations, dizziness, clouded consciousness, shortness of breath, and chest pain may occur. This disease may also increase the risk of heart failure, dementia, stroke, etc. The repeatedly occurring arrhythmia is also called AF burden and may be defined by, for example, the duration of the longest AF arrhythmia, the number of AF arrhythmias, the proportion of time that AF arrhythmias persist within a certain period. There are four types of AF. Namely, paroxysmal AF, persistent AF, long-standing persistent AF, and permanent AF. The type of AF depends on the frequency of AF occurrence and the patient's response to treatment. Short-term AF is paroxysmal AF, and this type of AF usually stops within 24 hours, but sometimes it may last up to about a week. Paroxysmal AF may occur repeatedly. Persistent AF is a condition where the arrhythmia lasts for more than a week. This may be spontaneous, but in most cases, treatment is required. In some cases, the arrhythmia may last for more than a year without disappearing. Even if pharmacological or other treatments are received several times to restore a normal pulse, the AF burden may not improve.

[0013] Although medical research has advanced significantly, the biological / physiological mechanisms regarding the progression of hypertension are not fully understood. For example, there is a hypothesis suggesting that when the blood supply to the brain decreases due to an increase in cerebrovascular resistance, hypertension progresses as a compensatory condition. Cerebral blood flow (CBF) in the brain is activated by arterial blood pressure and is inversely proportional to cerebrovascular resistance. For example, when the resistance to blood flow increases due to (cerebral) vascular diseases, arteriosclerosis, aging, etc., a compensatory increase in arterial blood pressure is essential to maintain cerebral perfusion (which is essential for maintaining the information processing function of brain nerve cells). Therefore, it is considered that by performing therapies or treatments aimed at improving cerebral blood flow in the brain, (general) cardiovascular diseases can be treated or the systemic arterial blood pressure (especially in hypertensive patients) can be lowered.

[0014] Blood flow to the brain originates from two sources. One is the internal carotid artery (supplying the front part of the brain), and the other is the vertebral artery (supplying the brainstem and the back part of the brain). These maintain cerebral circulation (blood flow within the brain). Cerebral circulation is the movement of blood through a dense network of cerebral arteries, blood, and veins. The speed of cerebral blood flow is about 750 milliliters per minute on average in healthy adults, but it becomes lower in certain disease states. This leads to the above-mentioned compensatory reaction.

Summary of the Invention

Problems to be Solved by the Invention

[0015] U.S. Patent Application Publication No. 2019351230 discloses an electrical stimulation device. This device includes means for generating an electrical stimulation generation control signal, means for outputting a music signal, a transcutaneous electrical signal generator, an electrical signal conditioner, and an electrode coupler. U.S. Patent Application Publication No. 2019351230 refers to a first electrode on the first surface of the tragus and a second electrode on the second surface of the tragus. These are used to provide a connection to a third electrode that contacts the skin of the ear canal. The current path disclosed in U.S. Patent Application Publication No. 2019351230 includes a current path between the first or second electrode and the third electrode.

Means for Solving the Problems

[0016] The present invention relates to an apparatus and method for non-invasively electrically stimulating cranial nerves protruding from the skin of the outer ear in order to regulate a user's cerebral blood flow. In some embodiments, the electrical stimulation is aimed at regulating the user's circulatory function, for example, regulating blood pressure or the function of the heart, and regulating electrical properties. One potential means of arterial blood pressure control is by regulating blood flow within the brain (particularly the brainstem; this region of the brain controls the circulatory system). According to the present invention, the above object can be achieved non-invasively by (electrically) stimulating the cutaneous sensory prominences of the skull and the spinal nerves (which originate in the brainstem and spinal cord). By activating these nerves, it is possible to promote blood flow through the lower-lying brainstem, and a decrease in arterial blood pressure and a reduction in the burden on the heart can be expected. The outer ear portion, particularly the tragus, is innervated by the sensory branches of the fifth (V) and tenth (X) cranial nerves and the branches of the spinal nerves C2 and C3. According to the present invention, by transdermally or percutaneously stimulating the sensory nerves protruding from the outer ear, it is possible to promote the overall cerebral blood flow (particularly the cerebral blood flow through the brainstem). According to a further aspect of the present invention, by electrically stimulating these nerves, a therapeutic effect against circulatory diseases can be exerted.

[0017] The present disclosure relates to the medical field in circulatory diseases including hypertension (i.e., high arterial blood pressure), pulmonary hypertension, left ventricular hypertrophy, and atrial fibrillation.

[0018] In a first aspect of the present invention, there is provided an apparatus for regulating a user's cerebral blood flow. The apparatus comprises a signal generator configured to generate an electrical stimulation signal, a controller connected to the signal generator and configured to determine the form of the electrical stimulation signal, and an earpiece (or a pair of earpieces) connected to the signal generator and the controller and provided with electrodes. The controller transmits the electrical stimulation signal to the electrodes. The electrodes are configured to be attached in contact with the user's tragus. The electrodes are configured to apply the electrical stimulation signal to the nerve that stimulates the user's tragus. The electrical stimulation signal includes continuous electrical pulses. Each of the electrical pulses repeats at a frequency of 1 Hz or more and 100 Hz or less. Each of the electrical pulses has a duration of 10 microseconds or more and 500 microseconds or less. Each of the electrical pulses has an intensity of 0.1 mA or more and 8 mA or less. The apparatus is used by the user for at least once a day for three consecutive days.

[0019] The apparatus may further comprise means for regulating the user's cerebral blood flow in order to lower the systemic arterial blood pressure, to improve left ventricular hypertrophy, to lower the pulmonary arterial blood pressure, to treat heart failure, or to treat atrial fibrillation.

[0020] In certain embodiments, the apparatus may be configured such that the electrical stimulation signal is provided to the user transdermally or percutaneously.

[0021] In some embodiments, the earpiece is configured to provide the electrical stimulation signal transdermally. The electrodes in such embodiments have a non-penetrating conductive surface. In some embodiments, the earpiece is configured to provide the electrical stimulation signal percutaneously. The electrodes in such embodiments have a conductive surface configured to penetrate the skin surface and make electrical contact with the underlying tissue surface.

[0022] In certain embodiments, the apparatus may be applied to the user for 5 minutes or more and 2 hours or less per day.

[0023] This device includes a first electrode and a second electrode. The first electrode is configured to be attached in contact with the user's left earlobe, and the second electrode may be configured to be attached in contact with the user's right earlobe. Further, this device may include a first earpiece and a second earpiece. The first earpiece includes the first electrode and a first reference electrode, and the second earpiece may include the second electrode and a second reference electrode.

[0024] In some embodiments, the first electrode is a first stimulating electrode, and the second electrode is a second stimulating electrode. Each of the earpieces includes a stimulating electrode and a reference electrode, and an electrical stimulation signal is applied between the stimulating electrode and the reference electrode.

[0025] This device may include a first electrode pair and a second electrode pair. The first electrode pair is configured to be attached in contact with the user's left earlobe, and the second electrode is configured to be attached in contact with the user's right earlobe. This device may include a first earpiece and a second earpiece. The first earpiece is configured to be attached in contact with the user's left earlobe and includes the first electrode pair. The second earpiece is configured to be attached in contact with the user's right earlobe and includes the second electrode pair. In each electrode pair, one electrode may be a stimulating electrode and the other electrode may be a reference electrode.

[0026] In some embodiments, the first earpiece and the second earpiece are substantially identical. In some embodiments, the first earpiece is shaped to fit the left tragus, and the second earpiece is shaped to fit the right tragus. In some embodiments, the left and right earpieces are substantially mirror symmetric to each other. In some embodiments, the earpiece is shaped to conform to the tragus portion or the other portion of the ear as follows. That is, by having the stimulating electrode contact the outer surface of the tragus and the reference electrode contact the inner surface of the tragus, the earpiece can preferentially fit the tragus. In some embodiments, the earpiece is shaped to conform to the tragus portion or the other portion of the ear as follows. That is, by having the stimulating electrode contact the inner surface of the tragus and the reference electrode contact the outer surface of the tragus, the earpiece can preferentially fit the tragus.

[0027] The apparatus may further comprise fixing means configured to fix the electrodes to the user's tragus. The fixing means may include a clip. The clip may comprise a first gripping portion and a second gripping portion. The first gripping portion and the second gripping portion are biased in a direction to contact each other. The stimulating electrode may be disposed on the first gripping portion (if a gripping portion exists).

[0028] There may be a reference electrode disposed on the first gripping portion or the second gripping portion.

[0029] This device may be provided with a physiological sensor configured to measure values of physiological parameters (e.g., heart rate, blood pressure, etc.). The physiological sensor may selectively store the measured values of the physiological parameters in the memory unit of this device. This device may further be provided with a temperature sensor configured to measure the value of the temperature of the user's skin. The temperature sensor may be configured to measure the value of the temperature of the skin of the tragus. This device may store the data measured by the temperature sensor in the memory unit of this device. The values stored in the memory unit may be used by the controller to determine the form of the electrical stimulation signal. In some embodiments, the physiological sensor or the temperature sensor may be disposed on the earpiece (e.g., on a clip).

[0030] In some embodiments, the measured values of the physiological sensor, the measured values of the temperature sensor, and information regarding the time and date of use are recorded and stored in the memory unit of this device.

[0031] This device may be provided with means for measuring the voltage applied between the stimulation electrode and the reference electrode, the current flowing between the stimulation electrode and the reference electrode, and the time relationship between these voltage and current.

[0032] This device may be provided with a stimulation electrode, a counter electrode, or a reference electrode. Further, this device may be configured to measure the voltage between the stimulation electrode and the reference electrode, and the voltage between the counter electrode and the reference electrode. In this way, the potential of the stimulation electrode, the counter electrode, or the reference electrode can be measured without the error (which is commonly seen in the prior art) caused by the voltage drop between the electrode and the skin.

[0033] In some embodiments, the device is configured to control the current flowing between the stimulation electrode and the reference electrode as a function of time, using feedback control means using one or more measured values, according to the form of the electrical stimulation signal. In some embodiments, the device is configured to control the voltage applied between the stimulation electrode and the reference electrode as a function of time, using feedback control means using one or more measured values, according to the form of the electrical stimulation signal.

[0034] In some embodiments, the device is configured to derive the phase relationship between the voltage applied between the stimulation electrode and the reference electrode and the current flowing between the stimulation electrode and the reference electrode, for example, to measure the electrical impedance of the tragus.

[0035] The measured value of the electrical impedance between the stimulation electrode and the reference electrode can be used to determine whether the electrodes are correctly placed on the opposing surfaces of the tragus, whether the device and method of the present invention are being used, and the time and duration when the device and method were used, and to control the voltage or current in response to the electrical impedance (e.g., to compensate for changes in the structure or conductivity of the tragus).

[0036] Furthermore, the measured values of the current, voltage, and phase relationship of the electrical stimulation signal may be stored in the memory unit of the device and used to determine the electrical impedance of the tragus.

[0037] The controller may be configured to generate an electrical stimulation signal and a stimulation pattern based on the user input received by the controller. This user input includes at least one of the pulse duration, pulse waveform, pulse frequency, pulse pattern, voltage intensity, and current intensity of the electrical stimulation signal.

[0038] The preferred features of the second (and subsequent) aspect of the present invention relate to the first aspect. The reverse is also true.

[0039] In a second aspect of the present invention, a system for providing non-invasive electrical stimulation to a nerve protruding from the outer ear is provided. In some embodiments, this system is intended to adjust the cerebral blood flow of the user. This system includes the device described in any of the above, and further includes a communication module connected to the controller. The communication module is configured to transmit information from the device to an external computer system and receive information from the external computer system. The information received from the external computer system is used by the controller to determine the form of the electrical stimulation signal.

[0040] This system may further be configured to operate simultaneously when information from the device is received by an external computer system. At this time, the information is compared with a second set of information stored in the external computer system to determine the operation to be performed by the device or the external computer system.

[0041] In a third aspect of the present invention, a method for regulating the cerebral blood flow of a user of the aforementioned device is provided. This method includes generating an electrical stimulation signal using a signal generator, determining the form of the electrical stimulation signal using a controller connected to the signal generator, and transmitting the electrical stimulation signal to an electrode. The electrode is configured to be attached in contact with the user's tragus. The electrode is configured to apply an electrical stimulation signal to the nerve that stimulates the user's tragus. The electrical stimulation signal includes continuous electrical pulses. Each of the electrical pulses repeats at a frequency of 1 Hz or more and 100 Hz or less. Each of the electrical pulses has a duration of 10 microseconds or more and 500 microseconds or less. Each of the electrical pulses has an intensity of 0.1 mA or more and 8 mA or less. The device is used by the user continuously for three days at least once a day.

[0042] In another embodiment, a method for non-invasively electrically stimulating a nerve protruding into the outer ear is provided using the aforementioned device. This method includes the steps of attaching a stimulation electrode and a reference electrode to contact the user's tragus, generating an electrical stimulation signal applied to the stimulation electrode and the reference electrode using the aforementioned device, and determining the waveform and frequency of the electrical stimulation signal using a controller. The electrical stimulation signal includes continuous electrical pulses. Each of the electrical pulses repeats at a frequency of about 1 Hz to about 100 Hz. Each of the electrical pulses has a duration of about 10 microseconds to about 500 microseconds and an intensity of about 0.1 mA to about 20 mA.

[0043] In some embodiments, the electrical stimulation signal includes continuous electrical pulses, each pulse repeating in a frequency range of about 3 Hz or more and about 50 Hz or less, and each pulse having a duration of about 100 microseconds or more and about 500 microseconds or less and an intensity of about 0.1 mA or more and about 8 mA or less.

[0044] In some embodiments, the frequency is in the range of about 1 Hz or more and about 100 Hz or less, for example, in the ranges of 1 Hz or more and 10 Hz or less, 10 Hz or more and 20 Hz or less, 20 Hz or more and 30 Hz or less, 30 Hz or more and 40 Hz or less, 40 Hz or more and 50 Hz or less, 50 Hz or more and 60 Hz or less, 60 Hz or more and 70 Hz or less, 70 Hz or more and 80 Hz or less, 80 Hz or more and 90 Hz or less, 90 Hz or more and 100 Hz or less.

[0045] In some embodiments, the frequency is in the ranges of 3 Hz or more and 20 Hz or less, 5 Hz or more and 30 Hz or less, 10 Hz or more and 50 Hz or less, 15 Hz or more and 60 Hz or less, 20 Hz or more and 75 Hz or less, 25 Hz or more and 80 Hz or less, 30 Hz or more and 100 Hz or less.

[0046] In some embodiments, the frequency is in the range of 3 Hz or more and 500 Hz or less.

[0047] In some embodiments, the pulse duration is in the range of about 10 milliseconds or more and about 500 milliseconds or less, for example, in the range of 10 milliseconds or more and 100 milliseconds or less, 20 milliseconds or more and 200 milliseconds or less, 30 milliseconds or more and 300 milliseconds or less, 40 milliseconds or more and 400 milliseconds or less, 50 milliseconds or more and 500 milliseconds or less.

[0048] In some embodiments, the pulse duration is in the range of 100 milliseconds or more and 200 milliseconds or less, 200 milliseconds or more and 300 milliseconds or less, 300 milliseconds or more and 400 milliseconds or less, 400 milliseconds or more and 500 milliseconds or less.

[0049] In some embodiments, the pulse duration is in the range of 50 milliseconds or more and 200 milliseconds or less, 100 milliseconds or more and 250 milliseconds or less, 200 milliseconds or more and 500 milliseconds or less.

[0050] In some embodiments, the pulse duration is in the range of 100 milliseconds or more and 500 milliseconds or less.

[0051] In some embodiments, the intensity is in the range of about 0.1 mA-seconds or more and about 10 mA or less, for example, in the range of about 0.1 mA-seconds or more and about 2 mA or less, about 0.2 mA-seconds or more and about 5 mA or less, about 0.5 mA-seconds or more and about 10 mA or less.

[0052] In some embodiments, the intensity is in the range of 0.1 mA-seconds or more and 1 mA or less, 0.2 mA-seconds or more and 2 mA or less, 0.3 mA-seconds or more and 3 mA or less, 0.4 mA-seconds or more and 4 mA or less, 0.5 mA-seconds or more and 5 mA or less, 0.6 mA-seconds or more and 6 mA or less, 0.7 mA-seconds or more and 7 mA or less, 0.8 mA-seconds or more and 8 mA or less, 0.9 mA-seconds or more and 9 mA or less, 1 mA-seconds or more and 10 mA or less.

[0053] In some embodiments, the intensity is in the range of 0.1 mA-seconds or more and 5 mA or less, 0.5 mA-seconds or more and 8 mA or less, 1 mA-seconds or more and 10 mA or less, 2 mA-seconds or more and 20 mA or less.

[0054] In some embodiments, the intensity is in the range of about 0.5 mA seconds or more and about 5 mA or less. In some embodiments, this method is applied to a user to adjust cerebral blood flow or for any of the purposes listed below. That is, the effects of systemic arterial blood pressure, improvement of left ventricular hypertrophy, reduction of pulmonary hypertension, treatment of cardiovascular diseases such as heart failure and atrial fibrillation, and the like.

[0055] In a fourth aspect of the present invention, a method for treating hypertension (high blood pressure), left ventricular hypertrophy, heart failure or atrial fibrillation is provided. This method includes the step of applying an electrical stimulation signal to a subject using the aforementioned device or method. Further, this method may be a method for simultaneously treating hypertension (high blood pressure), left ventricular hypertrophy, heart failure or atrial fibrillation. In some embodiments, this method is applied to regulate (e.g., increase) cerebral blood flow. The electrodes are configured to apply an electrical stimulation signal to the nerve that stimulates the tragus of the user. The electrical stimulation signal includes continuous electrical pulses. Each of the electrical pulses repeats at a frequency of 1 Hz or more and 100 Hz or less. Each of the electrical pulses has a duration of 10 microseconds or more and 500 microseconds or less. Each of the electrical pulses has an intensity of 0.1 mA or more and 8 mA or less. The device is used by the user for at least once a day for three consecutive days.

[0056] The stimulating electrode may be configured to be disposed on the skin on the outer surface of the outer ear, and the reference electrode may be configured to be disposed on the skin on the inner surface of the outer ear. In some embodiments, the electrical stimulation signal may be transmitted to the first electrode pair and the second electrode pair. At this time, the first electrode pair is attached in contact with the user's left earlobe, and the second electrode is attached in contact with the user's right earlobe. The electrical stimulation signals applied to the left and right earlobes may be substantially the same electrical stimulation signal. The electrical stimulation signals applied to the left and right earlobes may be applied to each of the left and right earlobes simultaneously or continuously. Alternatively, the electrical stimulation signal applied to the left earlobe is different from the electrical stimulation signal applied to the right earlobe, and the electrical stimulation signals applied to the left and right ears may be applied to each of the left and right earlobes simultaneously or continuously. Alternatively, the electrical stimulation signal applied to the left earlobe is different from the electrical stimulation signal applied to the right earlobe, and the electrical stimulation signal applied to the left earlobe may be applied at a different time from the electrical stimulation signal applied to the right earlobe.

[0057] The form of the electrical stimulation signal during use of the present device or application of the present treatment method may be a sine wave, square wave, triangular wave or "white noise" waveform. The form of the electrical stimulation signal may be a pulse waveform, and the pulse waveform may be substantially a sine wave, square wave, triangular wave or "white noise" waveform. The generated waveform may be a symmetric single-phase wave, symmetric two-phase wave or symmetric three-phase wave. Alternatively, the generated waveform may be an asymmetric single-phase wave, asymmetric two-phase wave or asymmetric three-phase wave.

[0058] This method can be applied to the user for 5 minutes or more and 2 hours or less per day.

[0059] This device can be applied to the user for 5 minutes or more and 2 hours or less per day.

[0060] This method and device can be applied to the user for 5 minutes or more and 2 hours or less per day, and this method is applied with an interval of at least one day.

[0061] The present method and apparatus can be applied to a user for 5 minutes or more and 2 hours or less per day, and this method may be applied at intervals of 1 day (24 hours) to 7 days (for example, about 1 day to 2 days).

[0062] In the treatment method according to the present invention, the present method or apparatus may be applied to a user for different periods as follows. That is, in an embodiment of the implementation of the treatment process according to the present invention, during a first period, this method is applied to the user for 5 minutes or more and 2 hours or less per day. Typically, the first period lasts for at least 3 days. However, in order to exert a therapeutic effect, depending on the needs of the user, the number of days on which this stimulation is given may be longer. During a second period, this method is stopped for at least 2 days. During a third period, this method is applied to the user for 5 minutes or more and 2 hours or less per day.

[0063] In a fifth aspect of the present invention, a method for treating a user's medical condition is provided. This method comprises the step of applying in combination to the user a pharmaceutical prescription and the apparatus and method of the present invention for performing non-invasive electrical stimulation on the nerves protruding from the skin of the outer ear. In some embodiments, the pharmacological effect of the drug is regulated by using the apparatus or method of the present invention.

[0064] The treatment method according to the present invention may include the step of pharmaceutically prescribing to a patient (user of the above apparatus) an active composition (for example, a drug for hypertension, heart failure or atrial fibrillation) for the treatment of hypertension, left ventricular hypertrophy, heart failure or atrial fibrillation. Furthermore, this method may be applied to symptoms including hypertension (high blood pressure), left ventricular hypertrophy, heart failure, and atrial fibrillation simultaneously. Such a pharmaceutically active composition may be given continuously or simultaneously separately from the use of the aforementioned apparatus.

[0065] Suitable antihypertensive agents may include diuretics, beta-adrenergic receptor blockers (β-blockers), angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, alpha-adrenergic receptor blockers (α-blockers), alpha II receptor blockers, or mixed alpha and beta blockers. For example, suitable drug active substances that can be used as antihypertensive agents include, but are not limited to, the following. That is, alfuzosin hydrochloride, ambrisentan, atenolol, bisoprolol, bosentan, clonidine hydrochloride, doxazosin, epoprostenol, furosemide, hydralazine hydrochloride, iloprost, indraline, macitentan, methyldopa, metoprolol, minoxidil, moxonidine, prazosin, propranolol, riociguat, sildenafil, sodium nitroprusside, tadalafil, tamsulosin hydrochloride, terazosin, etc.

[0066] Suitable drugs for treating heart failure may include diuretics, beta-adrenergic receptor blockers (β-blockers), angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers. Drugs that can be used as other heart failure treatments include, but are not limited to, heart rate lowering agents (e.g., ivabradine) and blood thinners (e.g., antiplatelet agents, anticoagulants). Suitable antiplatelet agents include, but are not limited to, the following. That is, anagrelide, aspirin, clopidogrel, prasugrel, ticagrelor, tirofiban, vorapaxar, dipyridamole, etc. Suitable anticoagulants include, but are not limited to, the following. That is, dabigatran, edoxaban, rivaroxaban, apixaban, warfarin, enoxaparin, dalteparin, fondaparinux, etc.

[0067] Antiarrhythmic drugs suitable for the treatment of atrial fibrillation include beta - adrenergic receptor blockers (β - blockers) (e.g., acebutolol, atenolol, betaxolol, labetalol, bisoprolol, carvedilol, metoprolol tartrate, metoprolol succinate, nebivolol, penbutolol, propranolol, sotalol hydrochloride, timolol, nadolol, pindolol), calcium channel blockers (e.g., verapamil hydrochloride, diltiazem hydrochloride), digitalis agents (e.g., digoxin), sodium channel blockers (e.g., disopyramide, mexiletine, quinidine, procainamide, propafenone, flecainide), potassium channel blockers (e.g., amiodarone, dronedarone, sotalol), etc.

[0068] This method may include the steps of measuring the user's blood pressure, determining whether the measured user's blood pressure is higher than a predetermined threshold, and, if the measured user's blood pressure is higher than the threshold, instructing a signal generator to generate an electrical stimulation signal.

[0069] The drug may be administered to the user in a dosage that exerts a therapeutic effect when combined with the method of the present invention. In some embodiments, the dosage may be selected from within the range known to exert a therapeutic effect in the prior art. In the case of the latter embodiments, the use of the device and method of the present invention is combined with the pharmacological mechanism of action of the drug so that the effectiveness of the drug is improved. Thus, a therapeutic effect is exerted by the combination of the method and the drug of the present invention. On the other hand, since the dosage can be reduced, the side effects caused by the drug are reduced.

[0070] The step of determining the form of the electrical stimulation signal using a controller connected to the signal generator includes the steps of determining the pulse duration, pulse frequency, waveform, and waveform pattern of the electrical stimulation signal.

[0071] A method for identifying a patient suitable for treatment using the apparatus and method of the present invention is also disclosed. This method includes the steps of recording an electrocardiogram of the patient for at least one minute, analyzing the power spectrum of the heart rate variation, determining the ratio (LF / HF) of the low frequency (LF) to the high frequency (HF) of the heart rate variation spectrum, and determining whether the LF / HF is higher than a predetermined threshold. In some embodiments, the predetermined threshold for LF / HF is 1 or about 1.

[0072] Another method for identifying a patient suitable for treatment using the apparatus and method of the present invention is also disclosed. This method includes the steps of recording a reference value of the patient's heart rate in a supine position, recording the patient's heart rate immediately after the patient stands up after recording the reference value of the heart rate, recording the patient's heart rate again in a standing position after a certain period of time, and determining whether the difference between the heart rate measured immediately after the patient stands up and the heart rate measured again after a certain period of time is less than a predetermined threshold. The predetermined threshold for the difference between the heart rate measured immediately after the patient stands up and the heart rate measured again after a certain period of time is 6 beats per minute.

[0073] Preferably, the patient lies supine for 5 to 15 minutes, optionally 5 to 10 minutes, preferably about 10 minutes. Preferably, the patient stands up vertically quickly in about 5 to 10 seconds, preferably 5 seconds. The recording of the heart rate when the patient first stands up is performed for about 1 to 5 minutes, preferably 1 to 3 minutes, preferably 1 minute. The recording of the heart rate measured again after a certain period of time is performed 10 to 30 seconds after standing up, preferably 10 to 20 seconds after standing up.

[0074] In one embodiment, it includes the steps of: recording the reference value of the patient's heart rate for one minute while the patient lies supine for 10 minutes; after recording the reference value of the heart rate, recording the patient's heart rate for one minute immediately after the patient stands up in 5 seconds; calculating the difference between the heart rate recorded in the standing state and the reference value of the heart rate recorded in the supine state; and determining whether the difference between the heart rate recorded immediately after the patient stands up and the heart rate recorded 10 to 20 seconds after standing up is less than a predetermined threshold value. The predetermined threshold value regarding the difference between the heart rate recorded immediately after the patient stands up and the heart rate recorded 10 to 20 seconds after standing up is 6 beats per minute.

[0075] Furthermore, the device and method of the present invention optionally include the step of pharmaceutically prescribing an active composition (for example, a drug for hypertension, heart failure or atrial fibrillation) for the treatment of hypertension, left ventricular hypertrophy, heart failure or atrial fibrillation to a patient (the user of the above device). Such a pharmaceutically active composition is as described above.

Brief Description of the Drawings

[0076] Various embodiments of the present invention will be described by way of example with reference to the following drawings.

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 1E

Figure 2

Figure 3A - 3B

Figure 4A - 4B

Figure 4C

Figure 5A - B

Figure 6

Figure 7A - 7B

Mode for Carrying Out the Invention

[0077] In this specification, the terms "subject", "individual" and "patient" refer to humans and do not mean a specific age or gender. In some embodiments, the individual subject may be a patient, particularly a person waiting for or a candidate for medical or other treatment (e.g., device-based neuromodulation described in this specification). In this specification, the term "about" means plus or minus 10% with respect to a quantity. For example, "about 5 mmHg" includes the range from 4.5 mmHg to 5.5 mmHg.

[0078] "Hypertension" The devices and methods of the present disclosure can be used for the treatment of hypertension in a subject, the reduction of arterial blood pressure, and the identification of a subject diagnosed with hypertension. The device or method of the present disclosure can also be used for the regulation of cerebral blood flow aimed at reducing the systemic arterial blood pressure of a subject and the identification of a subject diagnosed with hypertension. As used herein, hypertension is a conventionally known symptom or disease and refers to a state in which the systemic arterial blood pressure of a subject is chronically elevated.

[0079] To prevent, diagnose, and treat hypertension, blood pressure is classified into four stages: normal blood pressure (systolic blood pressure less than 120 mmHg and diastolic blood pressure less than 80 mmHg), high normal blood pressure (systolic blood pressure 120 - 129 mmHg and diastolic blood pressure less than 80 mmHg), stage 1 hypertension (systolic blood pressure 130 - 139 mmHg or diastolic blood pressure 80 - 89 mmHg), and stage 2 hypertension (systolic blood pressure 140 mmHg or higher or diastolic blood pressure 90 mmHg or higher). Patients whose diastolic blood pressure and systolic blood pressure belong to different classifications are classified into the higher stage (for example, a patient with 128 / 82 mmHg is diagnosed with stage 1 hypertension).

[0080] Hypertension may be a state where the systolic arterial blood pressure of a subject at rest exceeds 120 mmHg, or the diastolic blood pressure exceeds 80 mmHg. In some embodiments, hypertension may be a state where the systolic blood pressure of a subject at rest exceeds approximately the following threshold values. That is, a state of exceeding 115 mmHg, 120 mmHg, 125 mmHg, 130 mmHg, 140 mmHg, 145 mmHg, 150 mmHg, 155 mmHg, 160 mmHg, 165 mmHg, 170 mmHg. Alternatively, hypertension may be a state where the diastolic blood pressure of a subject at rest exceeds approximately the following threshold values. That is, a state of exceeding 80 mmHg, 85 mmHg, 90 mmHg, 95 mmHg, 100 mmHg, 105 mmHg, 110 mmHg, 115 mmHg, 120 mmHg. In some embodiments, systemic arterial hypertension may be chronic treatment-resistant hypertension. This may be defined as a persistent arterial blood pressure level exceeding the recommended target value (systolic blood pressure exceeding 130 mmHg under 24-hour ambulatory conditions) even though a documented treatment has been performed using at least three antihypertensive agents (one of which is diuretic) taken correctly. In some embodiments, the diagnosis of hypertension in a subject may be made by an individual having the qualification to make a diagnosis with specific authority.

[0081] When the left ventricular myocardial mass index (LVMI) exceeds 95 g / m in women 2 and exceeds 115 g / m in men 2 the subject is diagnosed with left ventricular hypertrophy.

[0082] [Pulmonary hypertension] The devices and methods of the present disclosure can also be used for the treatment of pulmonary hypertension. Pulmonary hypertension may be defined as a state where the systolic pulmonary artery blood pressure of a patient at rest exceeds about 25 mmHg.

[0083] [Heart failure] The devices and methods of the present disclosure can also be used for the treatment of heart failure. Heart failure, congestive heart failure, or chronic heart failure as used herein is a conventionally known condition or disease, referring to a state in which the heart cannot perform sufficient pumping function to maintain appropriate blood flow necessary for the body within organs or tissues. In some embodiments, heart failure may be defined as a state where the left ventricular ejection fraction of the subject is 50% or more (HFpEF), a state where it is 40% or more and 49% or less (heart failure with intermediate left ventricular ejection fraction), or a state where it is less than 40% (HFrEF).

[0084] [Atrial fibrillation] The devices and methods of the present disclosure can also be used for the treatment of atrial fibrillation, i.e., AF. AF is a well-known condition or disease, referring to a state in which disordered electrical stimuli (which are usually generated at the root of the pulmonary vein) exceed normal regular electrical stimuli (which are generated at the sinoatrial node of the right atrium). At this time, the electrical stimuli that generate the heartbeat become abnormal.

[0085] [Devices and methods for regulating cerebral blood flow] The present invention uses non-invasive neuromodulation devices and methods. This technique is based on adjusting cerebral blood flow by stimulating the tragus (e.g., the auricle) and applying electrical stimulation to the afferent (sensory) branches of the cranial nerves protruding into the brainstem. The purpose is to lower arterial blood pressure for the medical treatment of hypertension and left ventricular hypertrophy, and to reduce the ventricular workload for improving cardiac function, or to reduce the number and frequency of AF episodes for the medical treatment of heart failure. Furthermore, this device and method may be applied to the treatment of diseases in which several of hypertension (high blood pressure), left ventricular hypertrophy, heart failure, and atrial fibrillation occur simultaneously. For example, a patient with both hypertension and AF can be treated for both of these symptoms simultaneously by this device and method.

[0086] More specifically, the present invention realizes blood pressure reduction, reduction of left ventricular hypertrophy, and reduction of AF burden in hypertensive patients, and improves cardiac function in heart failure patients through non-invasive neuromodulation. This non-invasive neuromodulation constitutes a special stimulation treatment program. This stimulation treatment program provides electrical pulses having predetermined characteristics transdermally (to the skin) or percutaneously (using electrodes through the skin) to the inner and outer sides facing the tragus of both ears (FIG. 1A). The present invention, in the broadest sense, stimulates the tragus region of the outer ear to regulate cerebral blood flow. Thereby, the cranial and spinal nerve fibers are stimulated, the blood pressure of hypertensive patients is lowered, left ventricular hypertrophy is reduced, AF burden is reduced, and the cardiac function of heart failure is improved.

[0087] FIG. 1 shows the electrical stimulation positions for activating the nerves protruding from the skin of the tragus to regulate cerebral blood flow and treat cardiovascular diseases.

[0088] FIG. 1 shows an apparatus for regulating a user's cerebral blood flow. The apparatus includes a signal generator configured to generate an electrical stimulation signal, a controller connected to the signal generator and configured to determine the form of the electrical stimulation signal, and an earpiece connected to the signal generator and the controller. The earpiece includes a pair of electrodes, for example, a pair of a stimulation electrode and a reference electrode (see FIGS. 1B and 1C). The earpiece is connected to the signal generator and the controller via a wire. Alternatively, the earpiece may be connected to the signal generator and the controller via a wireless connection. In such an embodiment, the earpiece includes an earpiece signal generator for generating an electrical stimulation signal, a wireless receiver, and a power source. The earpiece signal generator receives commands from the receiver and is configured to apply an electrical stimulation signal to the stimulation electrode and the reference electrode.

[0089] The controller is configured to generate an electrical stimulation signal and a stimulation pattern based on user input received at the controller. Thus, the controller adjusts the parameters of the electrical stimulation signal according to the treatment plan required by the user. The controller may be connected to a communication module to convey information from an external information source to the controller. Alternatively, the controller may be directly controlled by the user of the device. The user input includes at least one of the pulse duration, waveform, pulse frequency, pulse pattern, and current intensity of the electrical stimulation signal. The user input may include information regarding the usage time of the device and the intervals of device usage in consecutive treatment rounds. For example, the device can inform the user that it should be used for 5 minutes to 2 hours per day for at least 3 consecutive days.

[0090] Figure 1A is a schematic diagram of a human head, showing the tragus 100 of each ear. The parts of particular interest in the present invention are the left and right tragus 100. Figure 1B shows the placement of the earpiece on the user's tragus. Figure 1C shows an embodiment of the earpiece in the form of an electrode clip. Figure 1D shows the earpiece of Figure 1C attached to the user's tragus. The same electrode pair can be taken for each of the left and right tragus, which is known as bilateral stimulation (to the left and right tragus). Using bilateral stimulation results in better outcomes compared to using stimulation of a single tragus. The first earpiece may be placed on the left tragus and the second earpiece may be placed on the right tragus. Thereby, a pair of stimulation electrode and reference electrode is arranged on each tragus. The stimulation electrode may be arranged on the outer skin surface of the tragus, and the reference electrode may be arranged on the inner skin surface of the tragus. With this device, both the left and right tragus are electrically stimulated for the purpose of regulating cerebral blood flow. The electrical stimulation signal generated by the device may be applied to each of the left and right tragus independently or simultaneously on the left and right.

[0091] The electrical stimulation signals applied to the left and right earlobes may be substantially the same electrical stimulation signals. That is, the electrical stimulation signals applied to the left and right earlobes may have substantially the same waveform. Alternatively, the electrical stimulation signal applied to the left earlobe may be different from the electrical stimulation signal applied to the right earlobe (i.e., the electrical stimulation signals applied to the left and right may have different waveforms). The electrical stimulation signals applied to the left and right earlobes may be applied to each of the left and right earlobes simultaneously or sequentially. "Simultaneously" means that the electrical stimulation signals are applied to the left and right earlobes at substantially the same time. "Sequentially" means that the electrical stimulation signal is first applied to one of the left and right earlobes and then subsequently applied to the other. This operation may be repeated multiple times (e.g., with an interval of 5 seconds) to continuously apply the electrical stimulation signals to each of the left and right earlobes alternately. Alternatively, the electrical stimulation signal may be applied to the left earlobe at a timing different from that at which it is applied to the right earlobe. "Different" means that the electrical stimulation signal is applied to only one of the left and right earlobes and not both simultaneously.

[0092] [Earpiece] In some embodiments, the earpiece is configured to provide a stimulation electrode in contact with the outer surface of the user's earlobe and a reference electrode in contact with the inner surface of the user's earlobe. In some embodiments, each earpiece includes only two electrodes.

[0093] In some embodiments, the earpiece includes only two current-carrying electrodes. In this case, the current-carrying electrodes are the stimulation electrode and the reference electrode. In some embodiments, the earpiece includes a stimulation electrode, a counter electrode, and a reference electrode. In this case, the current-carrying electrodes are the stimulation electrode and the counter electrode. And the reference electrode is operable by a controller that determines the electrical stimulation signal. In some embodiments, the earpiece is configured such that all three electrodes contact the tragus (e.g., the stimulation electrode and the reference electrode contact one side of the tragus, and the counter electrode contacts the other side of the tragus). In some embodiments, the earpiece is configured such that the stimulation electrode and the reference electrode contact the outer surface of the tragus, and the counter electrode contacts the inner surface of the tragus. In some embodiments, the earpiece is configured such that the stimulation electrode contacts one side of the tragus, and the reference electrode and the counter electrode contact the other side of the tragus.

[0094] In some embodiments, the stimulation electrode and the reference electrode are provided to the earpiece as follows. That is, when an electrical stimulation signal is applied with the stimulation electrode and the reference electrode in contact with the tragus, the current flowing between the stimulation electrode and the reference electrode mainly flows between the outer surface and the inner surface of the tragus through the tissue of the tragus.

[0095] In some embodiments, the earpiece is configured such that the current flowing between the stimulation electrode and the reference electrode flows only between the outer surface and the inner surface of the tragus through the tissue of the tragus. In this embodiment, the nerve that stimulates the surface or the internal tissue of the tragus is electrically excited by the potential difference between the stimulation electrode and the reference electrode, or the current flowing through the tissue surrounding the nerve.

[0096] In some embodiments, the electrical stimulation signal is selected such that there is a net normal current from the stimulation electrode to the reference electrode throughout the continuous period of the cyclically repeated pulses. In some embodiments, the net normal current from the stimulation electrode to the reference electrode is positive. In another embodiment, the net normal current from the stimulation electrode to the reference electrode is negative.

[0097] In some embodiments, the earpiece is configured as follows. That is, the stimulating electrode contacts the outer surface of the user's earlobe, the reference electrode contacts the inner surface of the user's earlobe, the electrical stimulation signal includes pulses that are cyclically repeated, and the electrical stimulation signal is selected such that there is a net normal current from the stimulating electrode to the reference electrode during each cycle.

[0098] In some embodiments, the stimulating electrode is the positive electrode, the reference electrode is the negative electrode, and the net current flows from the stimulating electrode towards the reference electrode. In another embodiment, the stimulating electrode is the negative electrode, the reference electrode is the positive electrode, and the net current flows from the reference electrode towards the stimulating electrode.

[0099] In some embodiments, the earpiece further comprises fixing means for holding the electrodes for a long time so as to fix the electrodes to the earlobe and enable treatment to be continuously performed on the user. The fixing means is configured to fix the earpiece and the electrodes on the skin of the earlobe. The fixing means may include a clip, or the earpiece itself may be in the form of a clip as shown in FIG. 1C. For example, in some embodiments, the clip may be configured to fix the earpiece electrode to the user's earlobe by gripping. In this case, the first gripping portion and the second gripping portion are on respective surfaces of the earlobe. In this case, the stimulating electrode may be in the first gripping portion and the reference electrode may be in the second gripping portion. Either the first gripping portion or the second gripping portion may extend into the ear canal. A physiological sensor may be disposed on the clip. Preferably, the physiological sensor is disposed on the first gripping portion or the second gripping portion. Alternatively, the physiological sensor may be in a part of the device (for example, a part of the earpiece that is not a clip).

[0100] In a preferred embodiment, the clip is shaped to ergonomically fit the earlobe. This is advantageous for the supply of electrical pulses and the monitoring of physiological parameters (such as heart rate and blood pressure), and can minimize noise in sensor signals related to movement (such as physiological signals like heart rate).

[0101] FIG. 1C shows an embodiment of the earpiece 101 in the form of an electrode clip. FIG. 1D shows a state where a clip provided with a stimulation electrode and a reference electrode is attached to the user's earlobe. In particular, the stimulation electrode 111 and the reference electrode 112 are incorporated into the earlobe clip 101. The earlobe clip 101 includes two lobes 101a and 101b. The lobes 101a and 101b are biased, for example, using a spring. Thereby, when the lobes 101a and 101b are attached to the user's earlobe 100, a gripping force is obtained. During use, the lobes 101a and 101b are arranged on both sides of the earlobe and hold the earlobe by being biased. The lobes 101a and 101b are arranged to face the skin of the earlobe. The lobe 101a includes the stimulation electrode 111 on its inner surface. And the opposite lobe 101b has the reference electrode 112 on its inner surface. These electrodes apply an electrical stimulation signal to the earlobe. The lobe 101a includes the stimulation electrode, and the opposite lobe 101b includes the reference electrode. These electrodes are configured to apply an electrical stimulation signal to the earlobe. Optionally, the earpiece includes a mark or shape for indicating the correct orientation of the earpiece to the user. Thereby, the stimulation electrode contacts the outer surface of the earlobe. For example, a mark 113 may be provided at a predetermined portion of the first lobe 101a. The earpiece 101 may include a physiological sensor 102. The physiological sensor 102 is configured to record the heart rate, blood pressure, or body temperature and store the value in the memory unit of the device. The earpiece may be configured such that the physiological sensor 102 contacts a predetermined portion of the outer ear (for example, the antitragus or a part of the auricle). The sensor 102 may be provided on the lobe 101a or 101b. In this case, the sensor is held in contact with the surface of the outer ear. The earpiece 101 is connected via a wire 103 to a device that generates an electrical signal. The earpiece may include wires 103a and 103b. The wires 103a and 103b each transmit a stimulation signal to the stimulation electrode and the reference electrode.

[0102] The clip includes a first gripping portion and a second gripping portion. The first gripping portion and the second gripping portion may correspond to two lobes 101a and 101b. A bias is applied to the lobes 101a and 101b to provide a gripping force on the user's earlobe 100. The stimulating electrode 111 is provided on the first gripping portion. The reference electrode 112 is provided on the second gripping portion. In some embodiments, the device includes a first electrode pair and a second electrode pair. In this case, the first electrode pair is configured to be disposed in contact with the user's left earlobe. And the second electrode pair is configured to be disposed in contact with the user's right earlobe. Further, the device includes a first earpiece and a second earpiece. At this time, the first earpiece includes the first electrode pair. The second earpiece includes the second electrode pair. In some embodiments, the first earpiece and the second earpiece are substantially identical. Therefore, the configuration shown in FIG. 1D can be applied to either the left or right ear. The electrical stimulation may be applied to only one ear or to both ears simultaneously. The earpiece is configured to be disposed in contact with the surfaces facing the outside and the inside of the earlobe. In one embodiment, the reference electrode is disposed in contact with the first surface of the earlobe, and the stimulating electrode is disposed in contact with the second surface of the earlobe. In some embodiments, the stimulating electrode is a positive electrode and contacts the second surface of the earlobe. And the reference electrode is a negative electrode and contacts the first surface of the earlobe. For example, the first surface of the earlobe may face inward (i.e., toward the user's head), and the second surface of the earlobe may face outward (i.e., away from the user's head). In some embodiments, the first surface of the earlobe may face outward, and the second surface of the earlobe may face inward.

[0103] Figure 1E is a cross-sectional view through the tragus 100 of a user wearing the earpiece 101 of Figure 1D. The first lobe 101a is disposed in contact with the outer surface 100a of the tragus, and the second lobe 101b is disposed in contact with the outer surface 100b of the tragus. The stimulating electrode 111 is in electrical contact with the skin surface outside the tragus. The reference electrode 112 is in electrical contact with the skin surface inside the tragus. A current I is shown. The current I flows through conductors 103a and 103b (connected to electrodes 111 and 112 respectively) to the generator. A first current path Id that travels substantially straight through the tissue of the tragus and a second current path Is that is mainly under (and near) the skin surface of the tragus are shown. The device of the present invention is configured such that the current resulting from the electrical stimulation signal flows substantially or completely confined within the tragus. Thereby the current mainly (in some embodiments, completely) flows through path Id or Is. This is different from conventional devices (i.e., in conventional devices, the electrodes are attached at another location on the human body and the current path is not confined within the tragus).

[0104] The electrodes may be arranged to contact the skin by means of a skin-permeable contact or a transcutaneous contact. Skin-permeable contact means that the electrode is placed on the skin but does not penetrate the skin. Transcutaneous contact means that the electrode has a needle or the electrode penetrates the skin directly. The needle or electrode penetrates the skin to apply an electrical stimulation signal to the user.

[0105] [Parts and Sensors of the Device] Additional measurements may be obtained using sensors. For example, the sensors may obtain characteristic sensor measurements such as body temperature and physiological parameters. These values may be used, for example, to determine whether the user is complying with the compliance matters regarding the device and method of the present invention (which may be defined by a physician or medical staff). The sensors may measure the body temperature to determine whether the device is in correct contact with the user's skin. Alternatively, the sensors may detect the user's heartbeat.

[0106] In some embodiments, the device measures physiological parameters and temperature parameters and stores their values in the memory unit of the device. The values of these parameters are stored together with date and time stamp information. This allows the records to be saved.

[0107] Optionally, the device may include an electrical circuit and a cardiovascular function sensor to measure and monitor the voltage, current, and phase relationship of an electrical stimulation signal. The measured values of the current, voltage, and phase relationship of the electrical stimulation signal are stored in the memory unit of the device. These values may be used to determine the electrical impedance of the earlobe. The measured value of the electrical impedance is used for detecting that the electrode is connected to the human body or for monitoring / measuring cardiovascular function. The electrical impedance may be stored in the memory unit of the device.

[0108] The information stored in the memory unit of the device can be used to determine an electrical stimulation signal, for example, by adjusting the waveform of the signal according to the information held in the memory. In some embodiments, the memory unit of the device may be accessed remotely or by a third party.

[0109] The device may further include a controller and a communication module connected to the memory unit of the device. The communication module is configured to transmit information from the device to an external computer system and receive information from the external computer system. This information can be used to inform the patient of the treatment plan and to determine compliance with the created treatment plan. The information received from the external computer system may be used by the controller to determine the form of the electrical stimulation signal. In this case, the electrical stimulation signal can be remotely controlled. The information shared via the communication module may include physiological measurement values and temperature measurement values obtained during use of the device. The communication module and the device together form a system for regulating the user's cerebral blood flow.

[0110] The device and the external computer system may further be configured to operate simultaneously when information from the device is received by the external computer system. At this time, the information is compared with a second set of information stored in the external computer system to determine an operation to be performed by the device or the external computer system.

[0111] [Experimental data] Figure 2 shows the values of the partial pressure of oxygen (PtO2) in the brain tissue (i.e., those recorded as measurements of cerebral blood flow) before, during, and after transcutaneous stimulation of the outer ear using the device and method of the present invention in experimental animals (laboratory rats). This experiment was conducted on rats that were anesthetized (urethane, 1.3 g / kg) and artificially ventilated. PtO2 was recorded in the cerebral cortex using an optical sensor based on fluorescence technology (which enables real-time recording of PtO2). In this experimental model, changes in cerebral PtO2 are similar to changes in cerebral blood flow and are used as a robust measurement of cerebral perfusion. Transcutaneous electrical stimulation of the outer ear was applied for 30 minutes using the following multiple stimulation parameters: namely, frequency 30 Hz, pulse width 50 microseconds; frequency 30 Hz, pulse width 2000 microseconds; frequency 30 Hz, pulse width 260 microseconds; frequency 3 Hz, pulse width 200 microseconds; frequency 30 Hz, pulse width 260 microseconds; frequency 3 Hz, pulse width 200 microseconds. The stimulation currents were set at 1 mA and 3 mA. The PtO2 values recorded in each animal and the standard error of the mean of the mean values ± are shown. It can be seen that non-invasive neuromodulation by transcutaneous electrical stimulation of the outer ear within a certain range of stimulation parameters can effectively achieve an increase in cerebral blood flow with a persistent effect. In this example, the stimulating electrode is placed on the skin on the outer surface of the outer ear, the reference electrode is placed on the skin on the inner surface of the outer ear, and a biphasic asymmetric pulse is used to effectively stimulate the sensory nerves of the outer ear (for example, as shown in Figure 7B).

[0112] Figure 3 shows the blood pressure values (individual data, n = 9) of patients with drug-resistant hypertension before and after using the device and method of the present invention. This experiment was conducted to verify the effect of transcutaneous electrical stimulation on the earlobe (which was given to patients with drug-resistant hypertension for at most 2 hours per day for at least 3 days) on blood pressure reduction. Patients diagnosed with drug-resistant hypertension showed office systolic blood pressure > 150 mmHg and ambulatory systolic blood pressure > 130 mmHg, despite taking the maximum allowable dosage of at least three antihypertensive drugs including diuretics. Transcutaneous earlobe electrical stimulation decreased both the 24-hour ambulatory systolic blood pressure (p = 0.0008; paired t-test; Figure 3A) and the 24-hour ambulatory diastolic blood pressure (p = 0.014; paired t-test; Figure 3B) of these patients. In this example, the stimulating electrode was placed on the skin on the outer surface of the earlobe, and the reference electrode was placed on the skin on the inner surface of the earlobe. Bilateral stimulation using a biphasic asymmetric pulse was used with the following parameters: frequency 3 Hz, pulse width 200 microseconds, and current 1 mA to 8 mA.

[0113] Figure 4 shows the blood pressure values (individual data, n = 10) of untreated hypertensive patients before and after using the device and method of the present invention. This experiment was conducted to verify the effect of transcutaneous electrical stimulation of the earlobe (which was given to untreated hypertensive patients for up to 2 hours per day for at least 3 days) on blood pressure reduction. Patients diagnosed with untreated hypertension were newly diagnosed hypertensive patients who had not received hypertension treatment in the past, had not been prescribed antihypertensive drugs, and had an office systolic blood pressure of 150 mmHg or more and less than 180 mmHg and a diastolic blood pressure of 80 mmHg or more (average of two of three measurements), or a daytime average systolic blood pressure of 120 mmHg or more and 160 mmHg or less and a daytime average diastolic blood pressure > 80 mmHg. Transcutaneous earlobe electrical stimulation decreased both the 24-hour ambulatory systolic blood pressure (p = 0.0026; paired t-test; Figure 4A) and the 24-hour ambulatory diastolic blood pressure (p = 0.004; paired t-test; Figure 4B) of these patients. In this example, the stimulating electrode was placed on the skin on the outer surface of the earlobe, and the reference electrode was placed on the skin on the inner surface of the earlobe. Bilateral stimulation using a biphasic asymmetric pulse was used with the following parameters: frequency 3 Hz, pulse width 200 microseconds, and current 1 mA to 8 mA.

[0114] As a particular example, in drug-resistant hypertensive patients (n = 9), when current pulses are continuously applied to the skin of both auricles (i.e., the left and right auricles) for at least 3 days and up to 2 hours per day, it can be seen from clinical data that the systolic blood pressure under 24-hour free activity (Figure 3A) and the diastolic blood pressure under 24-hour free activity (Figure 3B) are significantly reduced. The supply of current pulses to the auricles was performed over the entire auricle using stimulating electrodes and reference electrodes placed on each side of the auricle. Patients diagnosed with drug-resistant hypertension are those who show office systolic blood pressure > 150 mmHg and walking systolic blood pressure > 130 mmHg, despite taking the maximum allowable dosage of at least three antihypertensive drugs, including diuretics. Similarly, in untreated hypertensive patients (n = 10), when current pulses are continuously applied to the skin of both auricles (i.e., the left and right auricles) for at least 3 days and up to 2 hours per day, the systolic blood pressure under 24-hour free activity (Figure 4A) and the diastolic blood pressure under 24-hour free activity (Figure 4B) were significantly reduced. Patients diagnosed with untreated hypertension are newly diagnosed hypertensive patients who have never received hypertension treatment in the past and have never been prescribed antihypertensive drugs, and show office systolic blood pressure of 150 mmHg or more and less than 180 mmHg, diastolic blood pressure of 80 mmHg or more (average of two out of three measurements), or daytime average systolic blood pressure of 120 mmHg or more and 160 mmHg or less, daytime average diastolic blood pressure > 80 mmHg.

[0115] As another specific example, it has been found that non-invasive neuromodulation by the apparatus and method of the present invention can reduce left ventricular hypertrophy in untreated hypertensive patients. FIG. 4C shows the left ventricular myocardial weight (left ventricular myocardial weight coefficient) indexed against the left ventricular weight and body surface area of untreated hypertensive patients. Shown here are untreated hypertensive patients who received standard treatment (n = 5, showing individual data and the standard error of the mean of the mean ±) and untreated hypertensive patients before and 12 months after using the non-invasive neuromodulation device and method of the present invention (n = 3, showing individual data and the standard error of the mean of the mean ±). This experiment was conducted to verify the long-term effect of transcutaneous electrical stimulation of the auricle on left ventricular hypertrophy (evaluated by echocardiogram). Left ventricular hypertrophy is strongly correlated with hypertension. Transcutaneous auricular electrical stimulation was given daily for up to 2 hours for 10 days. Untreated hypertensive patients were diagnosed according to the above criteria. Five patients who received treatment according to current clinical guidance showed no change in left ventricular weight and left ventricular myocardial weight coefficient after 12 months (patient control group). On the other hand, all three patients (one male and two females) who received treatment using the apparatus and method of the present invention had a decrease in left ventricular weight and left ventricular myocardial weight coefficient recorded after 12 months (patient treatment group). In this example, the stimulating electrode was placed on the skin on the outer surface of the auricle, and the reference electrode was placed on the skin on the inner surface of the auricle. Bilateral stimulation using a biphasic asymmetric pulse was used with the following parameters: frequency 30 Hz, pulse width 200 microseconds, and current 1 mA to 8 mA.

[0116] As another particular example, unexpectedly, non-invasive neuromodulation by the apparatus and method of the present invention has been found to significantly and effectively lower arterial blood pressure when combined with pharmaceutical treatment. Such pharmaceutical treatment drugs include beta-adrenergic receptor blockers. This is effective even when the dosage of the beta-blocker used in combination is much lower than the dosage required for blood pressure reduction when the beta-blocker is used alone (Cochrane Database Syst Rev. 2016 3: CD007451). FIG. 5 shows the blood pressure values (individual data and mean ± standard error of the mean are shown, n = 4) of untreated hypertensive patients before and after using the apparatus and method of the present invention in combination with the pharmaceutical treatment of the beta-adrenergic receptor blocker bisoprolol. This experiment was conducted to verify the effect of blood pressure reduction when non-invasive neuromodulation according to the present invention (which was administered to untreated hypertensive patients for at most 2 hours per day for at least 3 days) was combined with bisoprolol (3 patients took 1.25 mg per day and 1 patient took 5 mg per day). Untreated hypertensive patients were diagnosed according to the above criteria. Electrical stimulation to the left and right tragus was administered continuously for at least 3 days, up to 2 hours per day. As a result, the office systolic blood pressure decreased (9 mmHg decrease; p = 0.047, paired t-test; FIG. 5A) and the office diastolic blood pressure decreased (11 mmHg decrease; p = 0.017, paired t-test; FIG. 5B). In this example, the stimulating electrodes were placed on the skin on the outer surface of the tragus, and the reference electrodes were placed on the skin on the inner surface of the tragus. Bilateral stimulation using a biphasic asymmetric pulse was used with the following parameters. Bilateral stimulation using a biphasic asymmetric pulse was used with the following parameters. The frequency was 30 Hz, the pulse width was 200 microseconds, and the current was 1 mA to 8 mA. Non-invasive neuromodulation of the present invention has been found to have a therapeutic effect of lowering systolic blood pressure when used in combination with beta-adrenergic receptor blockers. The effect of electrical stimulation of the tragus was significantly improved in patients receiving treatment with the beta-adrenergic receptor blocker bisoprolol.That is, office systolic blood pressure (decreased by 16 mmHg; p = 0.001, paired t-test; Figure 5A) and office diastolic blood pressure (decreased by 10 mmHg; p = 0.023, paired t-test; Figure 5B) further decreased. Thus, by combining non-invasive neuromodulation by transcutaneous bilateral tragus stimulation and systemic beta-adrenergic receptor blockers, the systolic and diastolic blood pressures of untreated hypertensive patients could be decreased by 25 mmHg and 22 mmHg, respectively. In this experiment, the dosage of bisoprolol was less than the dosage level at which a blood pressure-lowering therapeutic effect could be expected when used alone (Cochrane Database Syst Rev. 2016 3: CD007451). Therefore, it can be seen that the systemic blood pressure-lowering effect by the combination of non-invasive neuromodulation by transcutaneous bilateral tragus stimulation and systemic beta-adrenergic receptor blockers is greater than the sum of the effects of each treatment method performed separately.

[0117] In the case of patients with paroxysmal AF, by applying current pulses to the skin of both tragi, the frequency and duration of AF episodes could be reduced.

[0118] To achieve the effects exerted as a continuous decrease in arterial blood pressure in hypertensive patients, improvement of cardiac function in heart failure, or reduction of AF burden, electrical stimulation of the sensory innervation of the tragus required the use of current pulses with the following specific parameters. That is, a frequency of 1 - 30 Hz, an intensity of 0.1 - 8 mA, a pulse width of 10 - 250 microseconds, and square-shaped monophasic or biphasic symmetric or asymmetric pulses. Transcutaneous application of current pulses with a frequency of 1 - 30 Hz, an intensity of 0.1 - 8 mA, and a pulse width of 10 - 250 microseconds can reliably trigger the potential firing behavior of the subcutaneous nerve fibers that stimulate the tragus. Thereby, as shown in Figure 2, it is possible to achieve neuromodulation and improvement of cerebral blood flow. When the parameters of the applied current pulses are as follows, that is, when the frequency range is lower than 1 - 100 Hz or higher, the intensity range is lower than 0.1 - 8 mA or higher, and the pulse width is shorter or longer than 10 - 500 microseconds, no therapeutic effect can be obtained. Furthermore, to achieve a continuous decrease in arterial blood pressure in hypertensive patients, electrical stimulation of the sensory innervation of the tragus requires continuous treatment. This includes multiple sessions of the following stimulation treatment program. That is, in this stimulation treatment program, the stimulation is given simultaneously to the left and right (i.e., bilateral) tragi for 5 minutes to 2 hours per day, at least continuously for 3 days (initial course of treatment). Thereafter, the stimulation may be given simultaneously to the left and right (i.e., bilateral) tragi, up to 2 hours per session, once a week (once every 7 days) (continuous course of treatment). Alternatively, the stimulation may be given several times a day. For example, the device may be given to the user for a plurality of fixed periods per day. The total daily usage time of the device may be added up to 5 minutes to 2 hours.

[0119] The systemic blood pressure drop after the initial course of treatment was found to persist for several weeks. This is independent of whether the patient receives the next course of treatment. If the blood pressure does not drop after the initial course of treatment, an additional initial course of treatment (which may or may not be followed by a continued course of treatment by the patient) may be carried out to exert and maintain the therapeutic effect. This treatment cycle may be carried out periodically as long as the hypertensive state persists or as long as the therapeutic effect maintains the patient's health.

[0120] [Patient Screening] To identify patients who may be potential responders to the treatment according to the present invention, patients can be selected. For this purpose, an electrocardiogram of the patient for at least one minute is recorded, and the power spectrum of the heart rate change is analyzed to determine the ratio (LF / HF) of the low frequency (LF) to the high frequency (HF) of the heart rate change spectrum. By performing a neuromodulation method by stimulating the sensory innervation of the tragus, a blood pressure drop and improvement of left ventricular hypertrophy in hypertensive patients, and improvement of cardiac function in heart failure patients with LF / HF exceeding 1 are expected.

[0121] To identify patients who may be potential responders to the treatment according to the present invention, patients can also be selected by evaluating the recovery of heart rate after standing up. To perform this test, the patient lies quietly in a supine position for 10 minutes before the standing test. The supine position means lying horizontally with the face and body facing up. In this supine state, the reference values of heart rate, systolic blood pressure and diastolic blood pressure are recorded. Next, the patient stands up quickly (<5 seconds). After standing up, the heart rate, systolic blood pressure and diastolic blood pressure are recorded for 1 minute with a 10-second interval. The difference from the reference value is calculated by subtracting the reference value (the value of the heart rate measured in the supine position) from the heart rate value measured at each time point during standing. If the difference between the heart rate at 10 seconds after standing and the heart rate at 20 seconds after standing (heart rate recovery, i.e., the difference value from the peak heart rate immediately after standing) is less than 6 beats per minute in heart failure patients, a blood pressure drop in hypertension, improvement of left ventricular hypertrophy, and improvement of cardiac function can be expected by performing a neuromodulation method by stimulating the sensory innervation of the tragus.

[0122] [Parts of the device] A device for adjusting cerebral blood flow to treat cardiovascular diseases according to an embodiment includes at least one earpiece (preferably a pair of two earpieces) having a pair of electrodes, a signal generator connected to the pair of earpieces to generate an electrical stimulation signal, and a controller connected to the signal generator to determine the form of the electrical stimulation signal and the pattern of stimulation. The pair of electrodes consists of a stimulating electrode and a reference electrode. The stimulating electrode is configured to apply an electrical stimulation signal to the tragus. The reference electrode is configured to allow current to flow across the tragus. This device may selectively include the following configurations, namely, an electrical circuit and a cardiovascular function sensor for measuring and monitoring the voltage and current of a given signal and a cardiovascular physiological signal (e.g., ECG, blood pressure, etc.), a microcontroller or a computer, a memory, a user input keyboard, peripheral devices, a physiological sensor, a display element, a circuit for inputting, controlling, and recording data related to the use of the device, a device external to this device that can program this device or transmit data and information to / from this device, a wireless / wired communication system serving as an interface with a computer, a tablet, or a smartphone, etc. In this way, it is expected that by receiving treatment using the device including stimulation of the sensory innervation of the tragus according to the present invention, the cerebral blood flow of the patient is improved, the arterial blood pressure and left ventricular hypertrophy are reduced, the cardiovascular function is improved, etc. In a preferred embodiment, this device includes a first and a second earpiece, and stimulation of the sensory innervation of the tragus is performed on both traguses.

[0123] FIG. 6 is a block diagram of the apparatus according to the present invention. The signal generator 10 includes a signal / waveform generation unit 4, a controller 5, a memory 17, an auxiliary circuit 3, a user data input / control device 16 (for example, a keypad, a dial, an actuator / switch, etc.), a display device 15, and a communication module (wireless / wired communication) 6. The illustrated signal generator 10 includes a transmitter or other input / output circuit (i / o port) 12 of a communication module. The i / o port 12 enables the signal generation device 10 to communicate with another device 8. Thus, for example, the signal generation device 10 can be programmed or historical data recorded over time can be uploaded. The i / o port 12 may include a switch (for example, a mechanical switch, an electrical switch, an electromagnetic switch, etc.) for initializing a programmed stimulation algorithm (which may be activated by a physician, a medical professional, or a user).

[0124] The signal generator 10 applies a (stimulus program-determined) stimulus signal using a defined schedule to regulate the user's cerebral blood flow, lower arterial blood pressure, reduce left ventricular hypertrophy, or reduce the AF burden and improve cardiovascular function. In various embodiments, the device further comprises at least one port 12 that is part of the controller 4 or the microcontroller 5 for connecting at least one wire 13 (FIG. 6). This allows the wire 13 to be removed from the signal generator 10 and other wires to be used with the signal generator 10. The wire 13 may be used to connect to a physiological sensor or a temperature sensor. As described above, the signal generator 10 is for determining an electrical stimulus signal. More specifically, the signal generator 10 may be for determining time-course parameters related to a stimulation algorithm (e.g., pulse width, pulse frequency, waveform, waveform pattern, etc.). Examples of waveform patterns include, but are not limited to, sine waves, square waves, triangular waves, biphasic symmetric waves, biphasic asymmetric waves, "white noise" signals, etc. FIG. 7B shows some examples of stimulation waveforms that can be used to transcutaneously stimulate the auricular sensory innervation. The controller preferably generates electrical parameters of the stimulation algorithm (current or voltage intensity, frequency, burst frequency, waveform and duration, which are also called waveform parameters) based on the signals received and determined by the signal generator. The signal generator 10 may determine the waveform parameters based on the signals received from the sensors. This determination may be performed in three ways. The first is by user control using the display 15 or the input / control device 16. The second is automatically performed by a microcontroller according to pre-programmed computer-readable instructions determined by the microcontroller. The third is performed by programmed computer-readable instructions determined by an external computer 8.

[0125] The controller 4, the microcontroller 5, the memory 17, the auxiliary circuit 3, the user input / control device 16 (e.g., keypad, dial, switch, etc.), the display device 15, and the communication module (wireless or wired communication) 6 may be arranged within the same component (which may be an electronic device driven by a portable battery). The portable electronic device desirably can execute an application (or App), and preferably is a laptop computer, a tablet, or a smartphone 8. Alternatively, the signal generator 10 may be in the form of a portable electronic device or may be a separate component.

[0126] The controller 4 may further be connected to the auxiliary circuit 3 to apply an electrical stimulation signal to at least one electrode pair 1, 2 in order to stimulate at least one earlobe (preferably both earlobes) of a human when an appropriate signal is applied to the electrodes.

[0127] The stimulation algorithm is applied using a single wire and a single electrode on the wire. However, a plurality of wires and a plurality of electrodes on the wires may be used. The electrodes 1, 2 may be those of a wearable device and are preferably connected to the signal generator 10 via a wireless connection such as an electrical cable 14 or Bluetooth (registered trademark). In embodiments where a plurality of electrodes are used to stimulate the patient, the same or different waveforms may be applied to two or more electrodes. The two different waveforms may vary within a pattern or waveform parameter.

[0128] The signal generator may be an open-loop or closed-loop system and may be controlled by computer-readable instructions. In a closed-loop embodiment, a stimulation algorithm responsive to signals from the cardiovascular parameter sensor 7 may be applied. Here, the cardiovascular parameter sensor 7 may include one or more of the sensors enumerated below, namely, a blood pressure sensor, a temperature sensor, a pulse oximeter, an electrocardiogram sensor, a heart rate sensor, a temperature and tissue impedance sensor. These sensors detect parameters using electrodes connected to the human body or monitor / measure cardiovascular function. Using the detected parameters, a stimulation algorithm that continuously reduces blood pressure is applied. Thus, a closed-loop system can use information from cardiovascular sensors as a feedback mechanism or program. Thereby, the stimulation intensity can be reduced or increased, the waveform or waveform parameters can be changed or varied, and the physiological parameters measured during stimulation can be maintained at appropriate values below the upper limit and above the lower limit. In an open-loop embodiment, an external device 8 is used to apply a stimulation algorithm that continuously reduces blood pressure or adjusts waveform parameters. Further, in some embodiments, the signal generator is used to set the parameters of the stimulation signal. In some embodiments, the signal generator is used to change the parameters of the stimulation algorithm using the user data input device 16 or an external computer 8 to adjust the intensity of the stimulation.

[0129] The memory 11 (or memory section) includes computer-readable instructions that can be operated by a controller or a microcontroller to execute the functions of the device. Thus, in some embodiments, the signal generator can be used to execute the instructions. Thereby, an electrical stimulation signal can be provided based on a programmed stimulation algorithm to treat hypertension, heart failure, left ventricular hypertrophy, atrial fibrillation, and the like. Further, in some embodiments, the signal generator is used to set the stimulation signal parameters. In some embodiments, the signal generator is used to vary the parameters of the stimulation signal for the purpose of adjusting the intensity of the electrical stimulation signal. These are shown as the stimulation intensity in FIG. 7A.

[0130] The microcontroller and the memory device may include pre-programmed computer-readable instructions to implement a password or encryption function for restricting controlled electrical access to the signal generator, execution security, access to the device and stored data / stored information (such as user and maintenance instructions, device data required by law or regulation, etc.).

[0131] In some embodiments, one or more physiological parameters of a patient may be measured using sensors such as cardiovascular sensors and recorded by the device. Further, some of these measurements may be taken at different times during one stimulation period or at different times over multiple stimulation periods to determine a numerical value or range of numerical values of the physiological parameter. In one embodiment, the voltage or current intensity of the electrical stimulation signal and their phase relationships may be used to determine the electrical impedance of the patient's skin and may be recorded by the device. Thus, the numerical values or ranges of numerical values of such physiological parameters recorded in relation to the use of the device (date, time, waveform and waveform parameters) during the stimulation algorithm period may be recorded and combined. Thereby, a data set representing the use of the device by the patient is formed. In this way, information regarding the use of the device by the patient is provided and recorded. This information may further be reported to an external device. At this time, this information may be used to monitor the patient's condition or to show or provide evidence that the patient is complying with a stimulation / therapy program (which is determined by a physician, medical professional, or by a health management contract or insurance contract with a third party). Further, in some embodiments, the individual usage data set may be accessed remotely using a communication module. This enables remote monitoring of the patient, verification of whether the patient is complying with a health management plan / therapy plan, application of an initial and continuous course of stimulation, application of a stimulation algorithm to change a defined therapy plan, etc.

[0132] In some embodiments, the device may communicate with an external computer, tablet, or smartphone. Thereby, the external computer, tablet, or smartphone can communicate with a cardiovascular function monitor (e.g., a blood pressure monitor, a heart rate monitor, or an ECG monitor) to record personal usage data and data obtained from the cardiovascular function monitor. A physician or medical professional can verify the patient's cardiovascular values and advise the patient remotely (via the Internet or other telecommunications / computer networks) about an initial or ongoing course of treatment, or can determine the actions to be performed by the device or the external computer.

[0133] In some embodiments, the personal usage data may be analyzed for the purpose of determining whether the patient has used the device as determined by a physician or medical professional, or whether the patient has complied with the terms of an insurance policy. Thereby, the personal usage data is used to determine the occurrence of a penalty, a change in insurance premiums, the presence or absence of a change in insurance benefits or other coverage.

[0134] The device may include a plurality of stimulation electrodes on one earpiece, and may include a plurality of reference electrodes corresponding to each stimulation electrode or a single reference electrode corresponding to a plurality of stimulation electrodes on a given earpiece. In particular, there may be a plurality of stimulation electrodes configured to apply an electrical stimulation signal to the tragus.

[0135] [Pulse waveform] As shown in FIG. 7A, the electrical stimulation signal has intensity, waveform, pulse width, and frequency. The intensity is the strength or amplitude of the signal waveform (the difference between the maximum and minimum values of the waveform) expressed in volts or amperes. The frequency is the number of times the waveform repeats per second and is expressed in Hz. The pulse width is the duration of time from the start to the end of the waveform itself and is expressed in seconds. A square wave is shown in FIG. 7A. FIG. 7B shows some examples of stimulation pulse waveforms that can be used for percutaneous auricular tragus sensory nerve innervation stimulation. However, it is not limited to this, and the waveform may be in any form including a sine wave, square wave, triangular wave, biphasic wave, or "white noise" waveform.

[0136] The generated waveform may be a symmetric single-phase wave, symmetric biphasic wave, or symmetric three-phase wave. The generated waveform may be an asymmetric single-phase wave, asymmetric biphasic wave, or asymmetric three-phase wave. The waveform may be in any other form.

[0137] In some embodiments, the electrical stimulation signal may include a pulse waveform of a complex digital phase that repeats cyclically. In this case, the intensity or phase duration of the pulse when the signal at the stimulation electrode is positive with respect to the signal at the reference electrode is greater than the intensity or phase duration of the pulse when the signal at the stimulation electrode is negative with respect to the signal at the reference electrode.

[0138] In this case, a net normal current is applied during the duration of the pulse when the stimulation electrode is positive with respect to the reference electrode.

[0139] In some embodiments, the electrical stimulation signal may include a pulse waveform of a complex digital phase that repeats cyclically. In this case, the intensity or phase duration of the pulse when the signal at the stimulation electrode is positive with respect to the signal at the reference electrode is less than the intensity or phase duration of the pulse when the signal at the stimulation electrode is negative with respect to the signal at the reference electrode.

[0140] In this case, a net normal current is applied during the duration of the pulse when the stimulation electrode is negative with respect to the reference electrode.

[0141] In some embodiments, the multi-phase pulse waveform is a two-phase pulse waveform. In some embodiments, the multi-phase pulse waveform is a three-phase pulse waveform.

[0142] In some embodiments, the electrical stimulation signal may include a pulse waveform that circulates and repeats including a plurality of pulses. In this case, the intensity or duration of the pulse when the signal at the stimulating electrode is positive with respect to the signal at the reference electrode is greater than the intensity or duration of the pulse when the signal at the stimulating electrode is negative with respect to the signal at the reference electrode.

[0143] In this case, a net normal current is applied during the duration of the pulse such that the stimulating electrode is positive with respect to the reference electrode.

[0144] In some embodiments, the electrical stimulation signal may include a pulse waveform that circulates and repeats including a plurality of pulses. In this case, the intensity or duration of the pulse when the signal at the stimulating electrode is positive with respect to the signal at the reference electrode is less than the intensity or duration of the pulse when the signal at the stimulating electrode is negative with respect to the signal at the reference electrode.

[0145] In this case, a net normal current is applied during the duration of the pulse such that the stimulating electrode is negative with respect to the reference electrode.

[0146] [Method] A method is provided for non-invasively electrically stimulating a nerve protruding from the outer ear using the aforementioned device. This method includes steps of attaching a stimulating electrode and a reference electrode to contact the user's tragus, generating an electrical stimulation signal applied to the stimulating electrode and the reference electrode using the aforementioned device, and determining the waveform and frequency of the electrical stimulation signal using a controller. The electrical stimulation signal includes continuous electrical pulses. Each of the electrical pulses repeats at a frequency of about 1 Hz to about 100 Hz. Each of the electrical pulses has a duration of about 10 microseconds to about 500 microseconds and an intensity of about 0.1 mA to about 20 mA.

[0147] In some embodiments, the parameters of the pulse frequency, pulse duration, and intensity are selected to be within the ranges disclosed herein.

[0148] In some embodiments, the method includes applying an electrical stimulation signal to the user's tragus. Thereby, the current between the stimulation electrode and the reference electrode mainly flows through the tissue of the tragus. The current flowing through the tissue that does not form the tragus can be ignored.

[0149] In some embodiments, the method includes applying an electrical stimulation signal to the user's tragus. Thereby, the current between the stimulation electrode and the reference electrode mainly or exclusively flows between the outer and inner surfaces of the tragus through the tissue of the tragus.

[0150] In some embodiments, the electrical stimulation signal includes continuous pulses that are cyclically repeated. The electrical stimulation signal is selected such that a net normal current flows from the stimulation electrode towards the reference electrode during each cycle.

[0151] In some embodiments, the electrical stimulation signal is selected such that a net normal current flows from the stimulation electrode towards the reference electrode throughout the entire period of the continuous pulses that are cyclically repeated.

[0152] In some embodiments, the net normal current is positive. In some embodiments, the net normal current is negative.

[0153] In some embodiments, the electrical stimulation signal includes a multi-phase pulse waveform that is cyclically repeated. In this case, the intensity or phase duration of the pulse when the signal at the stimulation electrode is positive relative to the signal at the reference electrode is greater than the intensity or phase duration of the pulse when the signal at the stimulation electrode is negative relative to the signal at the reference electrode. In this case, a net normal current is provided during the duration of the pulse such that the stimulation electrode is positive relative to the reference electrode.

[0154] In some embodiments, the electrical stimulation signal includes a pulsed waveform of a complex phase that repeats cyclically. In this case, the intensity or phase duration of the pulse when the signal at the stimulation electrode is positive with respect to the signal at the reference electrode is smaller than the intensity or phase duration of the pulse when the signal at the stimulation electrode is negative with respect to the signal at the reference electrode.

[0155] In this case, a net normal current is applied during the duration of the pulse such that the stimulation electrode is negative with respect to the reference electrode.

[0156] In some embodiments, the pulsed waveform of the complex phase is a two-phase pulsed waveform. In some embodiments, the pulsed waveform of the complex phase is a three-phase pulsed waveform.

[0157] In some embodiments, the electrical stimulation signal includes a pulsed waveform that repeats cyclically and includes a plurality of pulses. In this case, the intensity or phase duration of the pulse when the signal at the stimulation electrode is positive with respect to the signal at the reference electrode is greater than the intensity or phase duration of the pulse when the signal at the stimulation electrode is negative with respect to the signal at the reference electrode. In this case, a net normal current is applied during the duration of the pulse such that the stimulation electrode is positive with respect to the reference electrode.

[0158] In some embodiments, the electrical stimulation signal includes a pulsed waveform that repeats cyclically and includes a plurality of pulses. In this case, the intensity or phase duration of the pulse when the signal at the stimulation electrode is positive with respect to the signal at the reference electrode is smaller than the intensity or phase duration of the pulse when the signal at the stimulation electrode is negative with respect to the signal at the reference electrode.

[0159] In this case, a net normal current is applied during the duration of the pulse such that the stimulation electrode is negative with respect to the reference electrode.

[0160] [Optimized treatment program (example)] To achieve the effects exerted as a continuous drop in arterial blood pressure in hypertensive patients, improvement in cardiac function in heart failure, or reduction in AF burden, it has been found that electrical stimulation to the sensory innervation of the tragus requires the use of current pulses having the following specific parameters. That is, the frequency is 1 - 30 Hz, the intensity is 0.1 - 8 mA, and the pulse width is 10 - 250 microseconds. It is desirable to apply stimulation to both traguses, that is, to the left and right traguses simultaneously, with square-shaped monophasic or biphasic symmetric or asymmetric pulses. Looking at the experimental results shown in Figure 2, the therapeutic effect is related to the improvement of cerebral blood flow and can be seen to be the result of such improvement. In particular, the therapeutic effect is exerted by using a frequency of 1 Hz or more and 10 Hz or less. Furthermore, the therapeutic effect is also exerted by using a frequency of 3 Hz or more and 50 Hz or less. Furthermore, the therapeutic effect is significantly exerted by using a pulse width of 10 microseconds or more and 500 microseconds or less and an intensity of 0.1 mA or more and 8 mA or less. The therapeutic effect is also exerted by using a pulse width of 100 microseconds or more and 500 microseconds or less. In some embodiments of the present method, only one of the stimulation parameters (frequency, intensity, pulse width) needs to be optimized. Therefore, it is not necessary to optimize all the parameters to produce a therapeutic effect. For example, in one embodiment, the electrical stimulation signal may include pulses that repeat at a frequency of 1 Hz to 100 Hz. At this time, each pulse may have a duration of 10 microseconds to 500 microseconds, or may have an intensity of 0.1 mA to 20 mA.

[0161] To be complete, in one embodiment, it is specified that the electrical stimulation signal includes continuous electrical pulses, each pulse is repeated in a frequency range of about 3 Hz or more and about 50 Hz or less, and each pulse has a duration of about 100 microseconds or more and about 500 microseconds or less and an intensity of about 0.1 mA or more and about 8 mA or less.

[0162] In some embodiments, the frequency ranges from about 1 Hz to about 100 Hz, for example, from 1 Hz to 10 Hz, from 10 Hz to 20 Hz, from 20 Hz to 30 Hz, from 30 Hz to 40 Hz, from 40 Hz to 50 Hz, from 50 Hz to 60 Hz, from 60 Hz to 70 Hz, from 70 Hz to 80 Hz, from 80 Hz to 90 Hz, from 90 Hz to 100 Hz.

[0163] In some embodiments, the frequency ranges from 3 Hz to 20 Hz, from 5 Hz to 30 Hz, from 10 Hz to 50 Hz, from 15 Hz to 60 Hz, from 20 Hz to 75 Hz, from 25 Hz to 80 Hz, from 30 Hz to 100 Hz.

[0164] In some embodiments, the frequency ranges from 3 Hz to 500 Hz. In some embodiments, the frequency ranges from about 3 Hz to about 35 Hz.

[0165] In some embodiments, the pulse duration ranges from about 10 milliseconds to about 500 milliseconds, for example, from 10 milliseconds to 100 milliseconds, from 20 milliseconds to 200 milliseconds, from 30 milliseconds to 300 milliseconds, from 40 milliseconds to 400 milliseconds, from 50 milliseconds to 500 milliseconds.

[0166] In some embodiments, the pulse duration ranges from 100 milliseconds to 200 milliseconds, from 200 milliseconds to 300 milliseconds, from 300 milliseconds to 400 milliseconds, from 400 milliseconds to 500 milliseconds.

[0167] In some embodiments, the pulse duration ranges from 50 milliseconds to 200 milliseconds, from 100 milliseconds to 250 milliseconds, from 200 milliseconds to 500 milliseconds.

[0168] In some embodiments, the pulse duration is in the range of 100 milliseconds or more and 500 milliseconds or less. In some embodiments, the pulse duration is in the range of 100 milliseconds or more and 300 milliseconds or less.

[0169] In some embodiments, the intensity is in the range of about 0.1 mA seconds or more and about 10 mA or less, for example, in the ranges of about 0.1 mA seconds or more and about 2 mA or less, about 0.2 mA seconds or more and about 5 mA or less, about 0.5 mA seconds or more and about 10 mA or less.

[0170] In some embodiments, the intensity is in the ranges of 0.1 mA seconds or more and 1 mA or less, 0.2 mA seconds or more and 2 mA or less, 0.3 mA seconds or more and 3 mA or less, 0.4 mA seconds or more and 4 mA or less, 0.5 mA seconds or more and 5 mA or less, 0.6 mA seconds or more and 6 mA or less, 0.7 mA seconds or more and 7 mA or less, 0.8 mA seconds or more and 8 mA or less, 0.9 mA seconds or more and 9 mA or less, 1 mA seconds or more and 10 mA or less.

[0171] In some embodiments, the intensity is in the ranges of 0.1 mA seconds or more and 5 mA or less, 0.5 mA seconds or more and 8 mA or less, 1 mA seconds or more and 10 mA or less.

[0172] In some embodiments, the intensity is in the range of about 0.5 mA seconds or more and about 5 mA or less.

[0173] In some embodiments, the intensity is in the range of about 0.1 mA seconds or more and about 20 mA or less.

[0174] To achieve cerebral blood flow regulation for improving the hypertensive state or left ventricular hypertrophy in hypertensive patients, neuromodulation by electrical stimulation of the sensory innervation of the tragus requires continuous treatment. This treatment includes a plurality of stimulation sessions according to the following stimulation treatment program. That is, the stimulation is given simultaneously (i.e., bilaterally) to the left and right tragus every day. The duration of the stimulation is 5 minutes or more and 2 hours or less per day, and this is continued for at least 3 days (initial course of treatment). The therapeutic effect can be optimized by applying this electrical tragus stimulation method to the user for at least 5 minutes and at most 2 hours per day. The electrical stimulation is given to the user with an interval of at least 1 day. Thereafter, the stimulation may be given simultaneously to the left and right tragus once a week (once every 7 days). The duration of the stimulation is at most 2 hours per session (continuous course of treatment).

[0175] A further treatment plan shown to be effective includes applying sensory innervation electrical stimulation to the user's tragus using different periods. During the first period, this method is applied to the user for 5 minutes or more and 2 hours or less per day. Typically, the first period lasts for at least 3 days. However, to exert the therapeutic effect, depending on the user's needs, the number of days this stimulation is given may be longer. During the second period, this method is stopped for at least 2 days. During the third period, this method is applied to the user for 5 minutes or more and 2 hours or less per day.

[0176] The use of the treatment device and method according to the present invention may be applied to the user in combination with any pharmaceutical treatment in accordance with the clinical guidelines for adjusting pharmaceutical effects.

[0177] Furthermore, in certain embodiments of this method, the user's treatment algorithm is adjusted according to the measured blood pressure values. Treatment may include continuous measurement of the patient's blood pressure. These measurements may then be compared to a predetermined threshold (e.g., a blood pressure level considered healthy). The threshold may be set by the user or by a third - party controller. The third - party controller may communicate with the device via a communication module. First, the user's blood pressure is measured and recorded in the memory section of the device. Next, the controller determines whether the user's blood pressure is higher than a predetermined threshold. If the user's blood pressure is higher than the predetermined threshold, an instruction to generate an electrical stimulation signal is sent to the signal generator.

[0178] The only currently officially recognized treatment for hypertension is taking pharmaceuticals. However, this may not be effective for some patients. Another major issue with pharmaceutical therapy is that since hypertension is a lifelong condition, patients have to take medicine for life. Many patients (45% of those receiving treatment) do not take the prescribed medicine. This is partly due to side effects and apathy. The technical advantage of the treatment method based on the device described in the claims is that this treatment is effective for drug - resistant patients and patients who cannot be managed with drugs. Also, according to the treatment method described in the claims, the patient can be treated in a short time or the device can be implanted. This treatment method is effective without the patient having to perform something for a long time or take medicine regularly. In the examples of the present disclosure, treatment including stimulation of the auricular - tragus sensory innervation can be applied to patients for 3 days to 2 weeks. In this case, in one patient, after performing the first course of treatment, the blood pressure remained reduced for several weeks. In another patient, after performing the first course of treatment, the blood pressure remained reduced for up to 12 months. Thereafter, this treatment can also be repeated. The treatment method described in the claims can also be used in combination with prescribed drugs.

[0179] Another advantage of the treatment method based on the device according to the claims is that it is possible to confirm whether the device has been used. This enables medical professionals to monitor whether the patient has used the device and complied with the prescribed treatment method. This monitoring can be performed remotely. The only way to do this using drugs is through blood / urine tests. However, this is time-consuming and costly. Continuing treatment correctly is a major issue for health insurance and public health funds. This is because maintaining blood pressure within the recommended range can significantly reduce the risks of stroke, myocardial infarction, renal failure, dementia, etc., and can significantly reduce the costs of lifelong health management and social care.

[0180] The features of the above aspects can be combined in any suitable way. The description of the above specific embodiments is merely illustrative. It will be understood by those skilled in the art that many improvements and modifications are possible. Furthermore, it will be understood that such improvements and modifications are also within the scope of the invention defined by the claims.

Claims

1. 1. An apparatus for regulating arterial blood pressure in a user, comprising: a signal generator configured to generate an electrical stimulation signal; a controller coupled to the signal generator and configured to determine a shape of the electrical stimulation signal; an earpiece connected to the signal generator and the controller and equipped with electrodes; Equipped with the earpiece comprises a stimulation electrode configured to apply an electrical stimulation signal to a nerve innervating the user's tragus; and a reference electrode; the earpiece is configured such that, when attached to the tragus, the stimulation electrode is positioned in contact with a first surface of the tragus and the reference electrode is positioned in contact with a second surface of the tragus opposite the first surface; the controller is configured to transmit the electrical stimulation signal to the stimulation electrodes; the electrode is configured to be attached in contact with the tragus of the user; the electrical stimulation signal comprises a train of electrical pulses; Each of the electrical pulses is repeated at a frequency of 1 Hz or more and 100 Hz or less, each of the electrical pulses having a duration of at least 10 microseconds and not more than 500 microseconds; Each of the electrical pulses has an intensity of at least 0.1 mA and not more than 8 mA.

2. 13. The device of claim 1, used to lower systemic arterial blood pressure.

3. 13. The device of claim 1, used to reduce pulmonary artery blood pressure.

4. 10. The device of claim 1, for use in treating hypertension.

5. 10. The device of claim 1, for use in treating pulmonary arterial hypertension.

6. 10. The device of claim 1, for use in treating heart failure.

7. 10. The device of claim 1, used for treating atrial fibrillation.

8. the stimulation electrodes are configured to provide the electrical stimulation signal to the user transcutaneously or transdermally; or 8. Apparatus according to any one of claims 1 to 7, characterized in that the stimulation electrodes are configured to deliver the electrical stimulation signal transcutaneously to the user.

9. a second earpiece including a second electrode and a second reference electrode; 8. An apparatus as claimed in any preceding claim, wherein the second earpiece is positioned to contact the tragus of the opposite ear of the user.

10. and further comprising a fastening means configured to fasten the electrode to the tragus of the user; Optionally, said fastening means comprises a clip; Optionally, the clip comprises a first gripping portion and a second gripping portion, the first gripping portion and the second gripping portion being biased into contact with each other; Optionally, the stimulation electrode is disposed on the first grip portion; 8. The device according to claim 1, wherein the reference electrode is selectively disposed in the second gripping portion.

11. 8. The device according to claim 1, further comprising a physiological sensor configured to measure values ​​of physiological parameters and to store the measured values ​​of physiological parameters in a memory portion of the device.

12. 12. The apparatus of claim 11, wherein the values ​​stored in the memory unit are used by the controller to determine the shape of the electrical stimulation signal.

13. 13. The device according to claim 11 or 12, wherein the physiological sensor is located on the earpiece.

14. 14. The apparatus of claim 11, wherein the physiological sensor senses a blood pressure of a user.

15. 15. A device according to any one of claims 11 to 14, arranged so that information regarding the physiological sensor measurements, the time and date of use are recorded and stored in a memory section of the device.

16. measurements of the current, voltage and phase relationship of the electrical stimulation signal are stored in a memory section of the device and used to determine the electrical impedance of the tragus; 16. The device of claim 15, wherein information regarding the electrical impedance of the tragus and the time and date of use is optionally stored in said memory portion.

17. the controller is configured to generate the electrical stimulation signal and a pattern of stimulation based on user input received at the controller; 17. The apparatus of claim 16, wherein the user input optionally includes at least one of a pulse duration, a pulse waveform, a pulse frequency, a pulse pattern, a voltage intensity, and a current intensity of the electrical stimulation signal.

18. the electrical stimulation signal is a pulse waveform comprising a continuous substantially square wave; 8. The apparatus according to claim 1, wherein the pulse waveform is one of a symmetric monophasic wave, a symmetric biphasic wave, an asymmetric monophasic wave, or an asymmetric biphasic wave.

19. the earpiece includes a marking or shape to indicate to a user the correct orientation of the earpiece; the stimulation electrode is a positive electrode; 8. The device according to claim 1, wherein the reference electrode is a negative electrode.

20. 1. A system for regulating arterial blood pressure of a user, comprising: The apparatus comprises an apparatus according to any one of claims 1 to 7, The apparatus further comprises a communications module connected to the controller; the communications module is configured to transmit information from the device to an external computer system and receive information from the external computer system; the information received from the external computer system is used by the controller to determine the shape of the electrical stimulation signal; Optionally, the information received from the external computer system is compared to a second set of information stored in the external computer system to determine an action to be performed by the device or the external computer system.

21. Measurement of the electrical impedance of the tragus is used to detect when the electrodes are connected to the body.

21. The system of claim 20, wherein information regarding the electrical impedance of the tragus and the time and date of use is stored in a memory portion.

22. 22. The system of claim 21, wherein the data stored in the memory unit includes a value or a range of values ​​of a physiological parameter measured by a physiological sensor, or a measured waveform or waveform parameter.

23. 23. A system according to any one of claims 20 to 22, characterized in that it is used to regulate the arterial blood pressure of a user.

24. 23. The system of any of claims 20 to 22, used to treat hypertension, pulmonary hypertension, heart failure or atrial fibrillation.

25. 8. An apparatus according to any one of claims 1 to 7, comprising: the first surface of the tragus is an outward facing surface of the tragus; The device, wherein the second surface of the tragus is an inward-facing surface of the tragus.

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