Neuromodulation for the treatment of cardiovascular diseases

Abstract

Apparatus and methods are provided for regulating cerebral blood flow in a user by stimulating the user's nerve. The modulation of cerebral blood flow can be performed for any of the following purposes: lowering systemic arterial blood pressure, reducing left ventricular hypertrophy, lowering pulmonary artery blood pressure, treating heart failure, or treating atrial fibrillation. An electrode is attached in contact with the user's tragus and configured to apply an electrical stimulation signal to the nerve innervating the user's tragus.

Description

[Technical field]

[0001] The present invention relates to a non-invasive neuromodulation device and method for regulating and improving blood flow in the brain (also referred to herein as cerebral blood flow). The technique is based on applying specially programmed electrical stimulation signals to cranial nerve cutaneous processes, which substantially reduces arterial blood pressure and left ventricular hypertrophy in subjects with arterial hypertension or improves cardiac function in subjects with heart failure. The present invention is also applicable to users seeking to lower systemic arterial blood pressure, reduce left ventricular hypertrophy, lower pulmonary artery blood pressure, treat heart failure or atrial fibrillation. [Background technology]

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

[0003] Left ventricular hypertrophy (LVH) is a condition in which there is an increase in myocardial mass. It is due to 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 condition in which blood pressure in the pulmonary arteries is chronically high.

[0005] Heart failure (also called "congestive heart failure," "congestive heart failure," or "chronic heart failure") is a condition in which the heart cannot pump adequately to maintain adequate blood flow within organs or tissues required by the body.

[0006] Atrial fibrillation (also known as AF) is a condition observed in patients experiencing arrhythmia characterized by rapid and irregular beating of the atria of the heart.

[0007] Globally, hypertension is a major health risk factor. Hypertension is associated with adverse cardiovascular events that increase the risk of myocardial infarction, heart failure, aneurysm, renal failure, and stroke. Managing hypertension is crucial. Every 10 mmHg reduction in blood pressure is associated with a 17% reduction in coronary artery disease, a 27% reduction in stroke, a 28% reduction in heart failure, and a 13% reduction in all-cause mortality. The American Heart Association guidelines define hypertension as a systolic blood pressure of 130 mmHg or higher or a diastolic blood pressure of 80 mmHg or higher. Applying these guidelines, 70.1 million people in the United States and 15 million people in the United Kingdom have hypertension in the 45-75 age group. This is more than 60% of the total population in this age group (J Am Coll Cardiol 71:e127, 2018). In Europe, only one-third of hypertensive patients are diagnosed and treated to achieve the recommended level of arterial blood pressure (Circulation 2016;134:441-450). When hypertension is secondary to another condition, it is generally prudent to treat the primary condition. There are various pharmacological treatments for hypertension. However, pharmacological treatments are often not fully effective. ~15% of all hypertensive patients are drug resistant (Hypertension. 2018;72:e53-e90), and the majority require two or more drugs. Efficacy is low in ~50% of all patients. Many patients require two or more drugs for blood pressure control, but more than 90% of these patients do not comply and fail to control blood pressure at the recommended level. Potential reasons include difficulty in accessing treatment, inappropriate dosing or combinations, patient reluctance to undergo treatment, co-administration with other drugs that interact, or treatment-resistant hypertension. Many hypertensive patients are reluctant to undergo pharmacological treatment. This is because some antihypertensive drugs can interfere with patients' daily lives or cause side effects, and some patients may prefer alternative medications for other reasons (BMJ 2012;345:e3953.).

[0008] Left ventricular hypertrophy (LVH) is present in 15% to 20% of the general population. The prevalence is further increased in the elderly, obese, and hypertensive patients. Two out of three patients with LVH have hypertension. According to an analysis of echocardiographic data from 37,700 patients, the prevalence is 19-48% in untreated hypertensive patients and 58-77% in high-risk hypertensive patients (J Hum Hypertens 26: 343-349, 2012). LVH is a compensatory hypertrophy, but ultimately an abnormal increase in left ventricular myocardial mass caused by chronic myocardial overload. The diagnosis of LVH is based on the assessment of left ventricular mass. Echocardiography is the test of choice for diagnosing LVH.

[0009] Echocardiography utilizes transthoracic or transesophageal placement of the transducer to measure the left ventricular end-diastolic diameter, posterior wall thickness, and interventricular septum thickness. From these measurements, along with the patient's height and weight, the left ventricular mass index can be calculated. Treatment of LVH must be aggressive because patients with LVH are at highest risk for cardiovascular morbidity and mortality. The goal of treatment is to reduce LVH and prevent left ventricular and heart failure. Antihypertensive therapy benefits patients by lowering arterial blood pressure and reducing the degree of LVH independently of blood pressure reduction, thereby reducing cardiovascular morbidity and mortality (Eur Heart J 39: 3021-3104, 2018).

[0010] Pulmonary hypertension comprises a group of serious clinical concepts, such as pulmonary arterial hypertension (PAH). In PAH, progressive loss or obstructive remodeling of the pulmonary vascular bed leads to elevated pulmonary arterial pressure and pulmonary vascular resistance. This leads to progressive right heart failure and right heart function deterioration. Pulmonary arterial hypertension is classified into five groups according to its cause: 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 blood clots Group 5: Pulmonary hypertension with other symptoms Current PAH treatments fail to target pulmonary vascular remodeling and inflammation, and there is an urgent need to better identify the underlying pathomechanisms of these conditions to support therapeutic innovations aimed at reversing the progressive pulmonary artery luminal narrowing, perivascular inflammation, and vascular loss, and regenerating normal pulmonary vasculature (Eur Respir J 53: 1801887, 2019).

[0011] Chronic heart failure (CHF) is one of the most common causes of morbidity and mortality in developed countries. Heart failure is associated with a wide range of complications. These include 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 heart's left ventricular drive fraction (LVEF). Heart disease with a normal LVEF (≥50%) is defined as CHF with preserved drive fraction (HFpEF), whereas CHF with a low LVEF (<40%) is defined as CHF with reduced drive fraction (HFrEF). The goals of heart disease treatment are to improve the patient's clinical status, functional capacity, and quality of life, and to reduce hospitalization and mortality. Established pharmacological treatment of HFrEF includes several drug classes (including beta-adrenergic receptor blockers (β-blockers), diuretics, and renin-angiotensin-aldosterone system inhibitors) and improves symptoms and reduces mortality. However, medical treatment remains inadequate because cardiac function declines over time and most patients have a poor prognosis. Furthermore, there is currently no cure for HFpEF, which represents an urgent clinical problem.

[0012] Atrial fibrillation (AF) is a condition observed in patients with arrhythmias characterized by rapid and irregular beating of the atria (also called episodes). It begins as short-term irregular beats, but as the disease progresses, it becomes more prolonged or persistent. It may also begin as another form of arrhythmia (such as atrial flutter) that progresses to AF. Often, AF arrhythmias are asymptomatic. Sometimes, symptoms include palpitations, dizziness, lightheadedness, shortness of breath, and chest pain. The disease may also increase the risk of heart failure, dementia, and stroke. The recurrent arrhythmias, also known as AF burden, may be defined by the duration of the longest AF arrhythmia, the number of AF arrhythmias, and the percentage of time that AF arrhythmias persist within a given period of time. There are four types of AF: paroxysmal AF, persistent AF, long-term persistent AF, and permanent AF. The type of AF depends on how often AF occurs and the patient's response to treatment. Short-term AF is paroxysmal AF, and this type of AF usually stops within 24 hours, but can sometimes last up to a week. Paroxysmal AF can also occur repeatedly. Persistent AF is when the arrhythmia lasts for more than a week. It can be spontaneous, but most require treatment. In some cases, the arrhythmia may persist for more than a year without disappearing. In some cases, AF burden does not improve despite multiple pharmacological and other treatments to restore a normal rhythm.

[0013] Although medical research has made great progress, the biological / physiological mechanisms of hypertension progression are not fully understood. For example, one hypothesis suggests that hypertension progresses as a compensatory condition when blood supply to the brain is reduced due to increased cerebrovascular resistance. Blood flow in the brain (cerebral blood flow) is activated by arterial blood pressure and is inversely proportional to cerebrovascular resistance. When resistance to blood flow increases due to (cerebro)vascular disease, arteriosclerosis, aging, etc., a compensatory increase in arterial blood pressure is essential to maintain cerebral perfusion (which is essential to maintain the information processing function of brain neurons). Therefore, it is believed that therapy or treatment aimed at improving blood flow in the brain can treat cardiovascular disease (in general) and lower systemic arterial blood pressure (especially in hypertensive patients).

[0014] Blood flow to the brain originates from two sources: the internal carotid arteries (supplying the front of the brain) and the vertebral arteries (supplying the brain stem and back of the brain). These maintain the cerebral circulation (blood flow within the brain). Cerebral circulation is the movement of blood through a dense network of cerebral arteries, blood vessels and veins. The rate of cerebral blood flow averages about 750 milliliters per minute in healthy adults, but can be lower in certain disease states. This leads to the compensatory responses described above. Summary of the Invention [Problem to be solved by the invention]

[0015] US2019351230 discloses an electrical stimulation device. The device includes a means for generating an electrical stimulation generating control signal, a means for outputting a music signal, a transcutaneous electrical signal generator, an electrical signal conduit, and an electrode coupler. US2019351230 refers to a first electrode on a first surface of the tragus and a second electrode on a second surface of the tragus, which are used to provide a connection to a third electrode that contacts the skin of the ear canal. The current path disclosed in US2019351230 includes a current path between the first or second electrode and the third electrode. [Means for solving the problem]

[0016] The present invention is directed to a device and method for non-invasively electrically stimulating cranial nerves projecting to the skin of the outer ear to regulate the user's cerebral blood flow. In some embodiments, the electrical stimulation is aimed at regulating the user's cardiovascular function, e.g., regulating blood pressure, regulating cardiac function, or regulating electrical properties. One potential means of arterial blood pressure control is through the regulation of blood flow in the brain, particularly the brainstem, as this region of the brain controls the cardiovascular system. In accordance with the present invention, this can be achieved non-invasively by (electrically) stimulating the cutaneous sensory projections of the skull and the spinal nerves, which originate in the brainstem and spinal cord. Activating these nerves can promote blood flow through the lower brainstem, which may lower arterial blood pressure and reduce cardiac strain. Parts of the outer ear, particularly the tragus, are innervated by the sensory branches of the fifth (V) and tenth (X) cranial nerves, as well as branches of spinal nerves C2 and C3. According to the present invention, the sensory nerves projecting to the outer ear can be stimulated transcutaneously or transcutaneously to promote overall cerebral blood flow, particularly through the brainstem. According to a further aspect of the present invention, electrical stimulation of these nerves can have a therapeutic effect on cardiovascular diseases.

[0017] The present disclosure relates to the field of medicine in cardiovascular disease, including hypertension (ie, high arterial blood pressure), pulmonary arterial hypertension, left ventricular hypertrophy and atrial fibrillation.

[0018] In a first aspect of the present invention, a device for regulating cerebral blood flow in a user is provided. The device comprises a signal generator configured to generate an electrical stimulation signal, a controller connected to the signal generator and configured to determine a shape of the electrical stimulation signal, and an earpiece (or pair of earpieces) connected to the signal generator and the controller and comprising an electrode. The controller transmits the electrical stimulation signal to the electrode. The electrode is configured to be attached in contact with the tragus of the user. The electrode is configured to apply the electrical stimulation signal to a nerve innervating the tragus of the user. The electrical stimulation signal comprises a series of electrical pulses. Each of the electrical pulses repeats at a frequency of ≧1 Hz and ≦100 Hz. Each of the electrical pulses has a duration of ≧10 microseconds and ≦500 microseconds. Each of the electrical pulses has an intensity of ≧0.1 mA and ≦8 mA. The device is used by the user at least once a day for three consecutive days.

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

[0020] In some embodiments, the device may be configured such that the electrical stimulation signal is delivered to the user transcutaneously or transdermally.

[0021] In some embodiments, the earpiece is configured to deliver the electrical stimulation signal transcutaneously. The electrodes in such embodiments have a non-penetrating conductive surface. In some embodiments, the earpiece is configured to deliver the electrical stimulation signal transcutaneously. The electrodes in such embodiments have a conductive surface configured to penetrate the skin surface and make electrical contact with a sub-surface layer of tissue.

[0022] In one embodiment, the device may be applied to the user for at least 5 minutes and up to 2 hours per day.

[0023] The device may comprise a first electrode and a second electrode, the first electrode configured for mounting in contact with the left tragus of a user and the second electrode configured for mounting in contact with the right tragus of a user. The device may further comprise a first earpiece and a second earpiece, the first earpiece comprising the first electrode and a first reference electrode, and the second earpiece comprising 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 comprises a stimulating electrode and a reference electrode, and an electrical stimulation signal is provided between the stimulating electrode and the reference electrode.

[0025] The 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 left tragus of a user and the second electrode pair is configured to be attached in contact with the right tragus of a user. The device may include a first earpiece and a second earpiece. The first earpiece is configured to be attached in contact with the left tragus of a user and includes the first electrode pair. The second earpiece is configured to be attached in contact with the right tragus of a user 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 images of each other. In some embodiments, the earpiece is shaped to conform to the tragus or the other part of the ear such that the stimulating electrode contacts the outer surface of the tragus and the reference electrode contacts the inner surface of the tragus, allowing the earpiece to preferentially fit the tragus. In some embodiments, the earpiece is shaped to conform to the tragus or the other part of the ear such that the stimulating electrode contacts the inner surface of the tragus and the reference electrode contacts the outer surface of the tragus, allowing the earpiece to preferentially fit the tragus.

[0027] The device may further comprise a fastening means configured to secure the electrode to the user's tragus. The fastening means may comprise 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 into contact with each other. The stimulation electrode may be disposed on the first gripping portion (if a gripping portion is present).

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

[0029] The device may comprise a physiological sensor configured to measure a value of a physiological parameter (e.g., heart rate, blood pressure, etc.). The physiological sensor may optionally store the value of the measured physiological parameter in a memory portion of the device. The device may further comprise a temperature sensor configured to measure a value of a temperature of the user's skin. The temperature sensor may be configured to measure a value of a skin temperature of the tragus. The device may store data measured by the temperature sensor in a memory portion of the device. The values ​​stored in the memory portion may be used by the controller to determine the shape of the electrical stimulation signal. In some embodiments, the physiological sensor or the temperature sensor may be located on the earpiece (e.g., on a clip).

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

[0031] The apparatus may comprise means for measuring the voltage applied between the stimulating and reference electrodes, the current flowing between the stimulating and reference electrodes, and the time relationship of these voltages and currents.

[0032] The device may include a stimulating electrode, a counter electrode, or a reference electrode. The device may further be configured to measure the voltage between the stimulating electrode and the reference electrode, and between the counter electrode and the reference electrode. In this way, the potential of the stimulating electrode, the counter electrode, or the reference electrode can be measured without errors due to the voltage drop between the electrode and the skin, which is common in the prior art.

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

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

[0035] Measurements of the electrical impedance between the stimulating and reference electrodes may be used to determine whether the electrodes are correctly positioned on opposing sides of the tragus, whether the devices and methods of the invention are being used, and when and for how long the devices and methods are being used, as well as to control voltage or current in response to that electrical impedance (e.g., to compensate for changes in the structure or conductivity of the tragus).

[0036] Additionally, measurements of the current, voltage and phase relationship of the electrical stimulation signal may be stored in the memory portion of the device and used to determine the electrical impedance of the tragus.

[0037] The controller may be configured to generate the electrical stimulation signal and the pattern of stimulation based on user input received at the controller, the user input including 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.

[0038] Preferred features of the second (and subsequent) aspects of the invention relate to the first aspect, and vice versa.

[0039] In a second aspect of the invention, a system is provided for non-invasive electrical stimulation of nerves projecting to the outer ear. In some embodiments, the system is intended to modulate cerebral blood flow in a user. The system comprises any of the devices described above, further comprising a communications module connected to a controller. The communications module is configured to transmit information from the device to an external computer system and to receive information from the external computer system. The information received from the external computer system is used by the controller to determine a shape of the electrical stimulation signal.

[0040] The system may be further configured to operate upon information being received by an external computer system from the device, where the information is compared to a second set of information stored in the external computer system to determine an action to be taken by the device or the external computer system.

[0041] In a third aspect of the invention, there is provided a method of regulating cerebral blood flow in a user of the aforementioned device. The method includes the steps of generating an electrical stimulation signal using a signal generator, determining a shape 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 tragus of the user. The electrode is configured to apply the electrical stimulation signal to a nerve innervating the tragus of the user. The electrical stimulation signal includes a series of electrical pulses. Each of the electrical pulses repeats at a frequency of greater than or equal to 1 Hz and less than or equal to 100 Hz. Each of the electrical pulses has a duration of greater than or equal to 10 microseconds and less than or equal to 500 microseconds. Each of the electrical pulses has an intensity of greater than or equal to 0.1 mA and less than or equal to 8 mA. The device is used by the user at least once a day for three consecutive days.

[0042] In another embodiment, a method is provided for applying non-invasive electrical stimulation to a nerve projecting to the outer ear using the device described above. The method includes attaching a stimulating electrode and a reference electrode to contact the tragus of a user, generating an electrical stimulation signal applied to the stimulating electrode and the reference electrode using the device described above, and determining a waveform and frequency of the electrical stimulation signal using a controller. The electrical stimulation signal includes a train of electrical pulses, each of which 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 comprises a train of electrical pulses, each pulse repeated at a frequency range of about 3 Hz to about 50 Hz, each pulse having a duration of about 100 microseconds to about 500 microseconds and an intensity of about 0.1 mA to about 8 mA.

[0044] In some embodiments, the frequency is in the range of about 1 Hz to about 100 Hz, e.g., 1 Hz to 10 Hz, 10 Hz to 20 Hz, 20 Hz to 30 Hz, 30 Hz to 40 Hz, 40 Hz to 50 Hz, 50 Hz to 60 Hz, 60 Hz to 70 Hz, 70 Hz to 80 Hz, 80 Hz to 90 Hz, or 90 Hz to 100 Hz.

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

[0046] In some embodiments, the frequency is in the range of 3 Hz to 500 Hz.

[0047] In some embodiments, the pulse duration is in the range of about 10 ms to about 500 ms, e.g., 10 ms to 100 ms, 20 ms to 200 ms, 30 ms to 300 ms, 40 ms to 400 ms, or 50 ms to 500 ms.

[0048] In some embodiments, the pulse duration is in the range of from 100 to 200 ms, from 200 to 300 ms, from 300 to 400 ms, or from 400 to 500 ms.

[0049] In some embodiments, the pulse duration is in the range of from 50 to 200 ms, from 100 to 250 ms, or from 200 to 500 ms.

[0050] In some embodiments, the pulse duration is in the range of 100 to 500 milliseconds.

[0051] In some embodiments, the intensity is in the range of about 0.1 mAsec to about 10 mA, e.g., about 0.1 mAsec to about 2 mA, about 0.2 mAsec to about 5 mA, or about 0.5 mAsec to about 10 mA.

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

[0053] In some embodiments, the intensity is in the range of 0.1 mAsec to 5 mA, 0.5 mAsec to 8 mA, 1 mAsec to 10 mA, or 2 mAsec to 20 mA.

[0054] In some embodiments, the intensity is in the range of about 0.5 mAsec to about 5 mA. In some embodiments, the method is administered to a user to regulate cerebral blood flow or for any of the following purposes: affecting systemic arterial blood pressure, improving left ventricular hypertrophy, reducing pulmonary arterial hypertension, treating cardiovascular diseases such as heart failure and atrial fibrillation, etc.

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

[0056] The stimulation electrode may be configured to be placed on the skin on the outer surface of the outer ear, and the reference electrode may be configured to be placed on the skin on the inner surface of the outer ear. In some embodiments, the electrical stimulation signal may be transmitted to a first electrode pair and a second electrode pair, where the first electrode pair is attached in contact with the user's left tragus and the second electrode pair is attached in contact with the user's right tragus. The electrical stimulation signals provided to the left and right tragus may be substantially identical electrical stimulation signals. The electrical stimulation signals provided to the left and right tragus may be provided simultaneously or sequentially to each of the left and right tragus. Alternatively, the electrical stimulation signal provided to the left tragus is different from the electrical stimulation signal provided to the right tragus, and the electrical stimulation signals provided to the left and right ears may be provided simultaneously or sequentially to each of the left and right tragus. Alternatively, the electrical stimulation signal applied to the left tragus may be different from the electrical stimulation signal applied to the right tragus, and the electrical stimulation signal applied to the left tragus may be applied at a different time than the electrical stimulation signal applied to the right tragus.

[0057] The shape of the electrical stimulation signal during use of the device or application of the treatment method may be a sine wave, a square wave, a triangular wave or a "white noise" waveform. The shape of the electrical stimulation signal may be a pulse waveform, which may be substantially a sine wave, a square wave, a triangular wave or a "white noise" waveform. The generated waveform may be a symmetric monophasic wave, a symmetric biphasic wave or a symmetric triphasic wave. Alternatively, the generated waveform may be an asymmetric monophasic wave, an asymmetric biphasic wave or an asymmetric triphasic wave.

[0058] The method may be applied to a user for at least 5 minutes and up to 2 hours per day.

[0059] The device may be applied to a user for at least 5 minutes and up to 2 hours per day.

[0060] The method and apparatus may be applied to a user for at least 5 minutes and up to 2 hours per day, the method being applied at intervals of at least one day.

[0061] The method and apparatus may be applied to a user for at least 5 minutes and up to 2 hours per day, and the method may be applied at intervals of 1 day (24 hours) to 7 days (e.g., about 1 to 2 days).

[0062] In the therapeutic method of the present invention, the method or device may be applied to the user for different time periods, as follows: In an embodiment of the therapeutic process of the present invention, during a first time period, the method is applied to the user for at least 5 minutes and up to 2 hours per day. Typically, the first time period lasts for a minimum of 3 days. However, the stimulation may be administered for a longer number of days, depending on the needs of the user to achieve a therapeutic effect. During a second time period, the method is discontinued for at least 2 days. During a third time period, the method is applied to the user for at least 5 minutes and up to 2 hours per day.

[0063] In a fifth aspect of the invention, a method of treating a medical condition in a user is provided, comprising administering to the user a device and method of the invention for non-invasive electrical stimulation of nerves projecting to the skin of the outer ear in combination with a drug prescription. In some embodiments, the pharmacological effect of the drug is modulated using the device or method of the invention.

[0064] The method of treatment according to the invention may comprise the step of pharmacopoeically prescribing to a patient (user of the device described above) an active composition for the treatment of hypertension, left ventricular hypertrophy, heart failure or atrial fibrillation (e.g. a hypertension, heart failure or atrial fibrillation drug). Furthermore, the method may be applied to conditions involving hypertension (high blood pressure), left ventricular hypertrophy, heart failure and atrial fibrillation simultaneously. Such pharmacopoeia may be given separately, sequentially or simultaneously with the use of the device described above.

[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 α and β blockers. For example, suitable pharmaceutical actives that can be used as antihypertensive agents include, but are not limited to, alfuzosin hydrochloride, ambrisentan, atenolol, bisoprolol, bosentan, clonidine hydrochloride, doxazosin, epoprostenol, furosemide, hydralazine hydrochloride, iloprost, indoramin, macitentan, methyldopa, metoprolol, minoxidil, moxonidine, prazosin, propranolol, riociguat, sildenafil, sodium nitroprusside, tadalafil, tamsulosin hydrochloride, terazosin, and the like.

[0066] Suitable heart failure medications may include diuretics, beta-adrenergic receptor blockers (β-blockers), angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers. Other drugs that may be used to treat heart failure include, but are not limited to, heart rate reducers (e.g., ivabradine), and blood thinners (e.g., antiplatelet agents, anticoagulants). Suitable antiplatelet agents include, but are not limited to, anagrelide, aspirin, clopidogrel, prasugrel, ticagrelor, tirofiban, Suitable anticoagulants include, but are not limited to, dabigatran, edoxaban, rivaroxaban, apixaban, warfarin, enoxaparin, dalteparin, fondaparinux, and the like.

[0067] Suitable antiarrhythmic drugs for treating 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), and the like.

[0068] The method may include measuring a user's blood pressure, determining whether the measured user's blood pressure is above a predetermined threshold, and instructing a signal generator to generate an electronic stimulation signal if the measured user's blood pressure is above the threshold.

[0069] The drug may be provided to the user in a dosage that, in combination with the method of the present invention, provides a therapeutic effect. In some embodiments, the dosage may be selected from a range known in the art to provide a therapeutic effect. In the latter embodiment, the use of the device and method of the present invention is combined with the pharmaceutical mechanism of action of the drug to enhance the efficacy of the drug. In this way, the combination of the method of the present invention and the drug provides a therapeutic effect, while reducing the side effects of the drug due to the lower dosage required.

[0070] Determining the shape of the electrical stimulation signal with a controller coupled to the signal generator includes determining the pulse duration, pulse frequency, waveform and waveform pattern of the electrical stimulation signal.

[0071] Further disclosed is a method for identifying a patient suitable for treatment with the devices and methods of the present invention, comprising the steps of recording an electrocardiogram of the patient for at least one minute, analyzing a power spectrum of the heart rate variability, determining a ratio of low frequency (LF) to high frequency (HF) (LF / HF) of the heart rate variability spectrum, and determining whether LF / HF is greater than a predetermined threshold. In some embodiments, the predetermined threshold for LF / HF is at or about 1.

[0072] A method of identifying a patient suitable for treatment with another of the apparatus and methods of the present invention is also disclosed, the method including the steps of recording a baseline heart rate of the patient while the patient is lying supine, recording the patient's heart rate immediately after the patient stands up after recording the baseline heart rate, recording the patient's heart rate again after a period of time while the patient is in a standing position, and determining whether the difference between the heart rate measured immediately after the patient stands up and the heart rate measured again after the period of time is less than a predetermined threshold, the predetermined threshold being 6 beats per minute.

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

[0074] In one embodiment, the method includes recording a baseline heart rate of the patient for 1 minute while the patient is lying supine for 10 minutes, recording the patient's heart rate for 1 minute immediately after the patient stands up 5 seconds after recording the baseline heart rate, calculating the difference between the heart rate recorded in the standing position and the baseline heart rate recorded while lying supine, 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. The predetermined threshold for 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] The devices and methods of the present invention further optionally include the step of pharmacologic prescribing to the patient (user of the device) an active composition for the treatment of hypertension, left ventricular hypertrophy, heart failure or atrial fibrillation (e.g., a hypertension, heart failure or atrial fibrillation medication), such as those described above. [Brief description of the drawings]

[0076] Various embodiments of the present invention will now be described, by way of example only, with reference to the following drawings, in which: [Figure 1A] 1 shows the left and right tragus of the human outer ear, which receive sensory nerve stimulation signals. Electrical stimulation of these nerves modulates blood flow in the brain transcutaneously or transcutaneously. In accordance with the present invention, this can be used to treat cardiovascular diseases. [Figure 1B] 1A-1C show an embodiment of an earpiece with an electrode clip. [Figure 1C] FIG. 2 shows an electrode clip. [Figure 1D] FIG. 1C shows the earpiece of FIG. 1B attached to the tragus. [Figure 1E] 1 is a cross-sectional view through the tragus with stimulating and reference electrodes attached, which contact the outer and inner surfaces of the tragus, respectively. The current path through the tragus is indicated. [Diagram 2]1 shows the changes in cerebral blood flow produced by non-invasive neuromodulation, which is applied in accordance with the present invention to an animal model using different parameters of electrical stimulation to the outer ear. [Figure 3A-3B] 1 shows blood pressure values ​​of a drug-resistant hypertensive patient before and after non-invasive neuromodulation using the device and method of the present invention. [Figure 4A-4B] 1 shows blood pressure values ​​of an uncontrolled hypertensive patient before and after non-invasive neuromodulation using the device and method of the present invention; [Figure 4C] 1 shows left ventricular mass in an uncontrolled hypertensive patient before and 12 months after non-invasive neuromodulation using the device and method of the present invention. [Figure 5A-B] 1 shows blood pressure values ​​of a patient with uncontrolled hypertension, before and after non-invasive neuromodulation using the device and method of the present invention, which was performed in combination with the beta-adrenergic receptor blockade bisoprolol. [Figure 6] FIG. 1 is a block diagram of an apparatus according to the present invention; [Figure 7A-7B] FIG. 1 illustrates possible waveforms of electrical stimulation signals. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0077] As used herein, the terms "subject," "individual," and "patient" refer to a human being and do not denote a particular age or sex. In some embodiments, an individual subject may be a patient, particularly a candidate for or for a medical or other treatment (e.g., device-based neuromodulation as described herein). As used herein, the term "about" refers to a quantity, plus or minus 10%. For example, "about 5 mmHg" includes the range of 4.5 mmHg to 5.5 mmHg.

[0078] "Hypertension" The disclosed devices and methods can be used to treat hypertension in a subject, to reduce arterial blood pressure, and to identify subjects diagnosed with hypertension. The disclosed devices or methods can also be used to regulate cerebral blood flow to reduce the subject's systemic arterial blood pressure, and to identify subjects diagnosed with hypertension. Hypertension, as used herein, is a known condition or disease that refers to a chronically elevated systemic arterial blood pressure in a subject.

[0079] To prevent, diagnose and treat hypertension, blood pressure is classified into four stages: normal (systolic blood pressure < 120mmHg and diastolic blood pressure < 80mmHg), high-normal (systolic blood pressure 120-129mmHg and diastolic blood pressure < 80mmHg), stage 1 hypertension (systolic blood pressure 130-139mmHg or diastolic blood pressure 80-89mmHg) and stage 2 hypertension (systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥ 90mmHg). Patients whose diastolic and systolic blood pressures fall into different categories are classified into the higher stage (e.g. a patient with 128 / 82mmHg is diagnosed with stage 1 hypertension).

[0080] Hypertension may be a condition in which a subject's systolic arterial blood pressure at rest exceeds 120 mmHg or diastolic blood pressure exceeds 80 mmHg. In some embodiments, hypertension may be a condition in which a subject's systolic blood pressure at rest exceeds approximately the following limits: 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 condition in which a subject's diastolic blood pressure at rest exceeds approximately the following limits: 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, which may be defined as a sustained arterial blood pressure level above recommended target (24-hour ambulatory systolic blood pressure above 130 mmHg) despite documented treatment with at least three correctly taken antihypertensive drugs, one of which is diuretic. In some embodiments, a diagnosis of hypertension in a subject may be made by an individual qualified to make such a diagnosis.

[0081] Left ventricular mass index (LVMI) of 95 g / m2 in women 2 If it exceeds 115g / m 2 If the blood pressure exceeds 100 MPa, the subject is diagnosed with left ventricular hypertrophy.

[0082] [Pulmonary arterial hypertension] The disclosed devices and methods may also be used to treat pulmonary arterial hypertension, which may be defined as a condition in which a patient's systolic pulmonary artery blood pressure exceeds about 25 mmHg at rest.

[0083] [heart failure] The disclosed devices and methods may also be used to treat heart failure. As used herein, heart failure, congestive heart failure, or chronic heart failure is a condition or disease known in the art that refers to the inability of the heart to pump adequately to maintain adequate blood flow within organs or tissues required by the body. In some embodiments, heart failure may be defined as a condition in which a subject's left ventricular drive fraction is greater than or equal to about 50% (HFpEF), greater than or equal to about 40% to less than or equal to 49% (HF with intermediate left ventricular drive fraction), or less than 40% (HFrEF).

[0084] [Atrial fibrillation] The disclosed devices and methods may also be used to treat atrial fibrillation, or AF. AF is a well-known condition or disease in which unregulated electrical impulses (usually generated at the root of the pulmonary artery) exceed the normal orderly electrical impulses (usually generated at the sinoatrial node in the right atrium). The electrical impulses that generate heartbeats then become abnormal.

[0085] [Device and method for regulating cerebral blood flow] The present invention uses a non-invasive neuromodulation device and method. This technique is based on stimulating the tragus (e.g., the auricle) and regulating cerebral blood flow by providing electrical stimulation to the afferent (sensory) branch of the cranial nerve projecting to the brainstem. The objective is to lower arterial blood pressure for the medical treatment of hypertension and left ventricular hypertrophy, and to reduce ventricular work to improve cardiac function or to reduce the number of AF episodes and their frequency for the medical treatment of heart failure. Furthermore, the device and method may be applied to the treatment of diseases in which some 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 simultaneously with the device and method.

[0086] More specifically, the present invention achieves a reduction in blood pressure, a reduction in left ventricular hypertrophy, and a reduction in AF burden in patients with hypertension through non-invasive neuromodulation, and improves cardiac function in patients with heart failure. This non-invasive neuromodulation constitutes a special stimulation therapy program. This stimulation therapy program involves the application of electrical pulses with predetermined characteristics transcutaneously (to the skin) or transcutaneously (using electrodes through the skin) to the inner and outer sides of the tragus of both ears (FIG. 1A). In the broadest sense, the present invention stimulates the tragus region of the outer ear to regulate cerebral blood flow. This stimulates cranial and spinal nerve fibers, which reduces blood pressure in patients with hypertension, reduces left ventricular hypertrophy, reduces AF burden, and improves cardiac function in patients with heart failure.

[0087] FIG. 1 shows electrical stimulation locations for activating nerves projecting to the skin of the tragus to regulate cerebral blood flow and treat cardiovascular disease.

[0088] FIG. 1 shows a device for regulating cerebral blood flow in a user. The device comprises a signal generator configured to generate an electrical stimulation signal, a controller connected to the signal generator and configured to determine the shape of the electrical stimulation signal, and an earpiece connected to the signal generator and the controller. The earpiece comprises a pair of electrodes, for example a stimulating electrode and a reference electrode (see FIG. 1B and FIG. 1C). The earpiece is connected to the signal generator and the controller via electrical leads. Alternatively, the earpiece may be connected to the signal generator and the controller via a wireless connection. In such an embodiment, the earpiece comprises an earpiece signal generator for generating an electrical stimulation signal, a wireless receiver, and a power source. The earpiece signal generator is configured to receive instructions from the receiver and provide the electrical stimulation signal to the stimulating electrode and the reference electrode.

[0089] The controller is configured to generate the electrical stimulation signal and the pattern of stimulation based on user input received at the controller. The controller thus 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 source to the controller. Alternatively, the controller may be directly controlled by a user of the device. The user input includes at least one of the pulse duration, waveform, pulse frequency, pulse pattern, and current strength of the electrical stimulation signal. The user input may include information regarding the time of use of the device and the interval between device use in successive treatment rounds. For example, the device may inform the user that the device should be used for 5 minutes to 2 hours per day for a minimum of 3 consecutive days.

[0090] FIG. 1A is a schematic diagram of a human head showing the tragus 100 of each ear. Particularly interesting for the present invention are the left and right tragus 100. FIG. 1B shows the placement of an earpiece on the user's tragus. FIG. 1C shows an embodiment of the earpiece in the form of an electrode clip. FIG. 1D shows the earpiece of FIG. 1C attached to the user's tragus. Identical electrode pairs can be placed on each of the left and right tragus, known as bilateral stimulation (on both the left and right tragus). Bilateral stimulation provides better results than stimulation of a single tragus. A first earpiece may be placed on the left tragus and a second earpiece on the right tragus. Thus, a pair of stimulating and reference electrodes is placed on each tragus. The stimulating electrode may be placed on the outer surface of the tragus and the reference electrode on the inner surface of the tragus. The device electrically stimulates both the left and right tragus for the purpose of regulating cerebral blood flow. The electrical stimulation signals generated by the device may be applied to the left and right tragus, either independently or simultaneously.

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

[0092] [Earpiece] In some embodiments, the earpieces are configured to present a stimulating electrode in contact with an outer surface of the user's tragus and a reference electrode in contact with an inner surface of the user's tragus, hi some embodiments, each earpiece comprises only two electrodes.

[0093] In some embodiments, the earpiece comprises only two current passing electrodes, where the current passing electrodes are a stimulating electrode and a reference electrode. In some embodiments, the earpiece comprises a stimulating electrode, a counter electrode, and a reference electrode, where the current passing electrodes are the stimulating electrode and the counter electrode, and the reference electrode is operable by a controller to determine the electrical stimulation signal. In some embodiments, the earpiece is configured such that all three electrodes contact the tragus (e.g., the stimulating 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 stimulating electrode and the reference electrode contact an outer surface of the tragus and the counter electrode contacts an inner surface of the tragus. In some embodiments, the earpiece is configured such that the stimulating electrode contacts one side of the tragus and the reference electrode contacts the other side of the tragus.

[0094] In some embodiments, the stimulating and reference electrodes are provided in the earpiece such that when an electrical stimulation signal is applied with the stimulating and reference electrodes in contact with the tragus, the current flowing between the stimulating and reference electrodes flows primarily through the tissue of the tragus between the outer and inner surfaces of the tragus.

[0095] In some embodiments, the earpiece is configured such that the current flowing between the stimulating electrode and the reference electrode flows only between the outer and inner surfaces of the tragus through the tissue of the tragus, in this embodiment, the nerve stimulating the surface, or the internal tissue of the tragus, is electrically excited by the potential difference between the stimulating 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 throughout the successive periods of the cyclically repeated pulses, there is a net normal current from the stimulating electrode to the reference electrode. In some embodiments, the net normal current from the stimulating electrode to the reference electrode is positive. In other embodiments, the net normal current from the stimulating electrode to the reference electrode is negative.

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

[0098] In some embodiments, the stimulating electrode is a positive electrode and the reference electrode is a negative electrode, and a net current flows from the stimulating electrode to the reference electrode, while in other embodiments, the stimulating electrode is a negative electrode and the reference electrode is a positive electrode, and a net current flows from the reference electrode to the stimulating electrode.

[0099] In some embodiments, the earpiece further comprises a fastening means for fastening the electrode to the tragus and holding the electrode over time so that the treatment is continuously administered to the user. The fastening means is configured to fasten the earpiece and the electrode on the skin of the tragus. The fastening 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 fasten the earpiece electrode to the tragus of the user by gripping. In this case, a first gripping portion and a second gripping portion are on respective sides of the tragus. In this case, the stimulating electrode may be on the first gripping portion and the reference electrode on 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 on a part of the device (e.g., the part of the earpiece that is not the clip).

[0100] In a preferred embodiment, the clip is shaped to fit ergonomically over the tragus, which is advantageous for delivery of electrical pulses and monitoring of physiological parameters (e.g., heart rate and blood pressure) while minimizing noise in the sensor signal (e.g., physiological signals such as heart rate) that is related to movement.

[0101] FIG. 1C shows an embodiment of an earpiece 101 in the form of an electrode clip. FIG. 1D shows the clip with the stimulating and reference electrodes attached to the tragus of a user. In particular, a stimulating electrode 111 and a reference electrode 112 are incorporated into the tragus clip 101. The tragus clip 101 comprises two lobes 101a and 101b. The lobes 101a and 101b are biased, for example with a spring, so that the lobes 101a and 101b have a gripping force when attached to the tragus 100 of a user. In use, the lobes 101a and 101b are positioned on either side of the tragus and biased to hold the tragus. The lobes 101a and 101b are positioned against the skin of the tragus. The lobe 101a includes a stimulating electrode 111 on its inner surface, and the opposite lobe 101b includes a reference electrode 112 on its inner surface. These electrodes provide an electrical stimulation signal to the tragus. The lobe 101a includes a stimulating electrode and the opposite lobe 101b includes a reference electrode. These electrodes are configured to provide an electrical stimulation signal to the tragus. Optionally, the earpiece is provided with a mark or shape to indicate to the user the correct orientation of the earpiece so that the stimulating electrode contacts the outer surface of the tragus. For example, a mark 113 may be provided on 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 values ​​in a memory portion of the device. The earpiece may be configured so that the physiological sensor 102 contacts a predetermined portion of the outer ear (e.g., the antitragus or a part of the pinna). 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 conductor 103 to a device that generates an electrical signal. The earpiece may include conductors 103a and 103b. Conductors 103a and 103b carry stimulation signals to the stimulation and reference electrodes, respectively.

[0102] The clip comprises 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. The lobes 101a and 101b are biased to provide a gripping force to the tragus 100 of the user. A stimulating electrode 111 is provided on the first gripping portion. A reference electrode 112 is provided on the second gripping portion. In some embodiments, the device comprises a first electrode pair and a second electrode pair, where the first electrode pair is configured to be placed in contact with the left tragus of the user, and the second electrode pair is configured to be placed in contact with the right tragus of the user. The device further comprises a first earpiece and a second earpiece, where the first earpiece comprises the first electrode pair and the second earpiece comprises the second electrode pair. In some embodiments, the first earpiece and the second earpiece are substantially identical. Thus, the configuration shown in FIG. 1D can be applied to either the left or right ear. Electrical stimulation may be provided to only one ear or to both ears simultaneously. The earpiece is configured to be placed in contact with the outward facing and inward facing surfaces of the tragus. In some embodiments, the reference electrode is placed in contact with a first surface of the tragus and the stimulation electrode is placed in contact with a second surface of the tragus. In some embodiments, the stimulation electrode is a positive electrode and is in contact with the second surface of the tragus, and the reference electrode is a negative electrode and is in contact with the first surface of the tragus. For example, the first surface of the tragus may face inward (i.e., toward the user's head) and the second surface of the tragus may face outward (i.e., away from the user's head). In some embodiments, the first surface of the tragus may face outward and the second surface of the tragus may face inward.

[0103] FIG. 1E is a cross-sectional view through the tragus 100 of a user wearing the earpiece 101 of FIG. 1D. The first lobe 101a is placed in contact with the outer surface 100a of the tragus, and the second lobe 101b is placed in contact with the outer surface 100b of the tragus. The stimulation electrode 111 is in electrical contact with the outer skin surface of the tragus. The reference electrode 112 is in electrical contact with the inner skin surface of the tragus. A current I is shown. The current I flows through leads 103a and 103b (connected to electrodes 111 and 112, respectively) to the generator. A first current path Id is shown, which runs approximately straight through the tissue of the tragus, and a second current path Is is shown, which is primarily below (and close to) the skin surface of the tragus. The device of the present invention is configured such that the current resulting from the electrical stimulation signal is substantially or completely confined to flow within the tragus. This causes the current to flow primarily (and in some embodiments, completely) through path Id or Is. This differs from conventional devices (wherein electrodes are attached elsewhere on the body and the current path is not confined to the tragus).

[0104] The electrodes may be placed in contact with the skin by transcutaneous contact or transdermal contact. Transcutaneous contact means that the electrodes are placed on the skin but do not penetrate the skin. Transcutaneous contact means that the electrodes have needles or that they directly penetrate the skin. The needles or electrodes penetrate the skin to provide an electrical stimulation signal to the user.

[0105] [Equipment parts and sensors] Additional measurements may be taken using the sensor. For example, the sensor may take 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 requirements for the device and method of the present invention, which may be prescribed by a doctor or medical staff. The sensor may measure body temperature to determine whether the device is in proper contact with the user's skin. Alternatively, the sensor may sense the user's heart rate.

[0106] In some embodiments, the device measures physiological and temperature parameters and stores the values ​​in the device's memory. The values ​​of these parameters are stored with date and time stamp information, allowing for a record to be kept.

[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 the electrical stimulation signal. The measurements of the current, voltage and phase relationship of the electrical stimulation signal are stored in a memory portion of the device. These values ​​may be used to determine the electrical impedance of the tragus. The measurements of the electrical impedance are used to detect that the electrodes are connected to the body or to monitor / measure cardiovascular function. The electrical impedance may be stored in a memory portion of the device.

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

[0109] The device may further comprise a communication module connected to the controller and to a memory portion of the device. The communication module is configured to transmit information from the device to and receive information from an external computer system. This information may be used to inform the patient of a treatment plan and may also be used 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 shape of the electrical stimulation signal. In this case, the electrical stimulation signal may be remotely controlled. Information shared via the communication module may include physiological and temperature measurements obtained during use of the device. The communication module and the device together form a system for regulating cerebral blood flow of a user.

[0110] The apparatus and the external computer system may further be configured to act upon information received by the external computer system from the device, where the information is compared to a second set of information stored in the external computer system to determine an action to be taken by the apparatus or the external computer system.

[0111] [Experimental data] FIG. 2 shows values ​​of partial pressure of oxygen (PtO2) in brain tissue (i.e. recorded as a measure of cerebral blood flow) before, during and after transcutaneous stimulation of the outer ear using the device and method of the present invention on an experimental animal (laboratory rat). The experiment was performed on anesthetized (urethane, 1.3 g / kg) and artificially ventilated rat. PtO2 was recorded in the cerebral cortex using an optical sensor based on fluorescence technology (allowing 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 measure of cerebral perfusion. Transcutaneous electrical stimulation of the outer ear was administered for 30 minutes using the following stimulation parameters: The simulation currents were set at 1 mA and 3 mA. The values ​​of PtO2 recorded in each animal and the mean ± standard error of the mean are shown. It can be seen that non-invasive neuromodulation by transcutaneous electrical stimulation of the outer ear given a certain range of stimulation parameters can effectively achieve an increase in cerebral blood flow with a sustained 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 (e.g., as shown in Figure 7B).

[0112] FIG. 3 shows 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 performed to verify the effect of transcutaneous electrical stimulation of the tragus (given for a maximum of 2 hours per day for at least 3 days to patients with drug-resistant hypertension) on lowering blood pressure. Patients diagnosed with drug-resistant hypertension are those who exhibit office systolic blood pressure >150 mmHg and ambulatory systolic blood pressure >130 mmHg despite taking the maximum tolerated dosage of at least three antihypertensive drugs, including diuretics. Transcutaneous electrical stimulation of the tragus lowered both the 24-hour ambulatory systolic blood pressure (p=0.0008; paired t-test; FIG. 3A) and the 24-hour ambulatory diastolic blood pressure (p=0.014; paired t-test; FIG. 3B) of these patients. In this example, the stimulation electrode was placed on the skin on the outer surface of the tragus and the reference electrode was placed on the skin on the inner surface of the tragus. Bilateral stimulation with biphasic asymmetric pulses was used with the following parameters: The frequency was 3 Hz, the pulse width was 200 microseconds, and the current was 1 mA to 8 mA.

[0113] FIG. 4 shows blood pressure values ​​(individual data, n=10) of patients with uncontrolled hypertension before and after using the device and method of the present invention. This experiment was conducted to verify the effect of transdermal electrical stimulation of the tragus (which was given to uncontrolled hypertension patients for up to 2 hours per day for at least 3 days) on lowering blood pressure. Patients diagnosed with uncontrolled hypertension are those who have not been previously treated for hypertension (newly diagnosed), have never been prescribed antihypertensive drugs, and have an office systolic blood pressure of 150 mmHg to 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 to 160 mmHg and a daytime average diastolic blood pressure >80 mmHg. Transcutaneous electrical stimulation of the tragus reduced both 24-h ambulatory systolic blood pressure (p=0.0026; paired t-test; Fig. 4A) and 24-h ambulatory diastolic blood pressure (p=0.004; paired t-test; Fig. 4B) in these patients. In this example, the stimulating electrode was placed on the skin on the outer surface of the tragus and the reference electrode was placed on the skin on the inner surface of the tragus. Bilateral stimulation was used with biphasic asymmetric pulses with the following parameters: frequency 3 Hz, pulse width 200 microseconds, and current 1 mA to 8 mA.

[0114] As a special example, clinical data show that in patients with drug-resistant hypertension (n=9), current pulses applied to the skin of both tragus (i.e., left and right tragus) for up to 2 hours each day for a minimum of 3 consecutive days significantly reduced 24-hour ambulatory systolic blood pressure (Figure 3A) and 24-hour ambulatory diastolic blood pressure (Figure 3B). Current pulses were delivered to the tragus across the entire tragus, with stimulating and reference electrodes placed on each side of the tragus. Patients diagnosed with drug-resistant hypertension were those who showed office systolic blood pressure >150mmHg and ambulatory systolic blood pressure >130mmHg despite taking the maximum permitted dosage of at least three antihypertensive drugs, including diuretics. Similarly, in patients with uncontrolled hypertension (n=10), electrical current pulses applied to the skin of both tragus (i.e., left and right tragus) for up to 2 hours each day for a minimum of 3 consecutive days significantly reduced 24-hour ambulatory systolic blood pressure (Figure 4A) and ambulatory diastolic blood pressure (Figure 4B). Patients diagnosed with uncontrolled hypertension were those with no previous hypertension treatment (newly diagnosed) and no prescription for antihypertensive medication, who had an office systolic blood pressure of 150mmHg to 180mmHg and a diastolic blood pressure of 80mmHg or more (average of two of three measurements) or a daytime mean systolic blood pressure of 120mmHg to 160mmHg and a daytime mean diastolic blood pressure >80mmHg.

[0115] As another specific example, it has been found that non-invasive neuromodulation with the device and method of the present invention can reduce left ventricular hypertrophy in patients with uncontrolled hypertension. FIG. 4C shows left ventricular mass and left ventricular myocardial mass indexed to body surface area in patients with uncontrolled hypertension. Shown are uncontrolled hypertensive patients receiving standard treatment (individual data and mean ± standard error of the mean shown, n=5) and uncontrolled hypertensive patients before and after 12 months of using the non-invasive neuromodulation device and method of the present invention (individual data and mean ± standard error of the mean shown, n=3). This experiment was performed to examine the long-term effect of transcutaneous electrical stimulation of the tragus on left ventricular hypertrophy (assessed by echocardiography). Left ventricular hypertrophy is strongly correlated with hypertension. Transcutaneous electrical stimulation of the tragus was given for up to 2 hours daily for 10 days. Uncontrolled hypertensive patients were diagnosed according to the criteria described above. Five patients treated according to current clinical guidance showed no change in left ventricular mass and left ventricular mass index after 12 months (control group of patients). In contrast, three patients (one male and two female) treated with the device and method of the present invention all recorded a decrease in left ventricular mass and left ventricular mass index after 12 months (treatment group of patients). In this example, the stimulation electrode was placed on the skin on the outer surface of the tragus and the reference electrode was placed on the skin on the inner surface of the tragus. Bilateral stimulation was used with biphasic asymmetric pulses with the following parameters: frequency 30 Hz, pulse width 200 microseconds, current 1 mA to 8 mA.

[0116] As another specific example, it was unexpectedly found that non-invasive neuromodulation according to the device and method of the present invention, when combined with pharmaceutical treatment, significantly reduces arterial blood pressure effectively. Such pharmaceutical treatment drugs include beta-adrenergic receptor blockers. This is effective even when the combined beta-blocker dose is much lower than the dose required to reduce blood pressure when used alone (Cochrane Database Syst Rev. 2016 3: CD007451). Figure 5 shows blood pressure values ​​(individual data and mean ± standard error of the mean are shown, n=4) of uncontrolled hypertensive patients before and after using the device and method of the present invention in combination with the pharmaceutical treatment of beta-adrenergic receptor blocker bisoprolol. This experiment was performed to verify the blood pressure reducing effect of non-invasive neuromodulation according to the present invention (which was given to uncontrolled hypertensive patients for a maximum of 2 hours daily for at least 3 days) in combination with bisoprolol (3 patients received 1.25 mg daily and 1 patient received 5 mg daily). Patients with uncontrolled hypertension were diagnosed according to the above criteria. Electrical stimulation of the left and right tragus was given for a maximum of 2 hours each day for at least 3 consecutive days. This resulted in a decrease in office systolic blood pressure (9 mmHg decrease; p=0.047, paired t-test; Fig. 5A) and office diastolic blood pressure (11 mmHg decrease; p=0.017, paired t-test; Fig. 5B). In this example, the stimulating electrode was placed on the skin on the outer surface of the tragus and the reference electrode was placed on the skin on the inner surface of the tragus. Bilateral stimulation with biphasic asymmetric pulses was used with the following parameters: frequency 30 Hz, pulse width 200 microseconds, current 1 mA to 8 mA. The non-invasive neuromodulation of the present invention was found to have therapeutic effect in lowering systolic blood pressure when used in combination with a beta-adrenergic receptor blocker. The effect of electrical stimulation of the tragus was significantly improved in patients treated with the beta-adrenergic receptor blocker bisoprolol.That is, the office systolic blood pressure (16 mmHg reduction; p = 0.001, paired t test; Fig. 5A) and the office diastolic blood pressure (10 mmHg reduction; p = 0.023, paired t test; Fig. 5B) were further reduced. Thus, the combination of noninvasive neuromodulation by transcutaneous bilateral tragus stimulation and systemic beta-adrenergic receptor blockade reduced systolic and diastolic blood pressure by 25 mmHg and 22 mmHg, respectively, in patients with uncontrolled hypertension. In this study, the dose of bisoprolol was lower than the dose level at which a therapeutic effect on blood pressure reduction can be expected when used alone (Cochrane Database Syst Rev. 2016 3: CD007451). Thus, the systemic blood pressure reduction effect of the combination of noninvasive neuromodulation by transcutaneous bilateral tragus stimulation and systemic beta-adrenergic receptor blockade is greater than the sum of the effects of each treatment separately.

[0117] In patients with paroxysmal AF, current pulses applied to the skin of both tragus ears reduced the frequency and duration of AF episodes.

[0118] To achieve the effect exerted as a sustained drop in arterial blood pressure in hypertensive patients, an improvement in cardiac function in heart failure or a reduction in AF load, electrical stimulation of the sensory innervation of the tragus required the use of current pulses with specific parameters: frequency 1-30Hz, intensity 0.1-8mA, pulse width 10-250 microseconds, square-shaped monophasic or biphasic symmetrical or asymmetrical pulses. Transcutaneous application of current pulses with frequency 1-30Hz, intensity 0.1-8mA and pulse width 10-250 microseconds can reliably induce the potential firing behavior of the subcutaneous nerve fibers innervating the tragus. This allows the realization of neuromodulation and improved cerebral blood flow, as shown in Figure 2. No therapeutic effect is obtained if the parameters of the applied current pulses are as follows: frequency range lower or higher than 1-100H, intensity range lower or higher than 0.1-8mA, pulse width shorter or longer than 10-500 microseconds. Furthermore, to achieve a sustained reduction 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 stimulation treatment program, in which stimulation is given simultaneously to the left and right (i.e., both) tragus for 5 minutes to 2 hours per day, daily for at least three consecutive days (initial course of treatment). Thereafter, stimulation may be given simultaneously to the left and right (i.e., both) tragus for up to 2 hours per session, once a week (once every 7 days) (continuous course of treatment). Alternatively, stimulation may be given several times a day. For example, the device may be given to the user for fixed periods of time per day. The total daily use time of the device may add up to 5 minutes to 2 hours.

[0119] The reduction in systemic blood pressure after the initial course of treatment has been found to persist for several weeks, regardless of whether the patient receives a subsequent course of treatment. If blood pressure does not decrease after the initial course of treatment, a further initial course of treatment (which may or may not be followed by a continuing course of treatment, depending on the patient) may be administered to achieve and maintain the therapeutic effect. This cycle of treatment may be administered periodically for as long as the hypertensive condition persists, or as long as the therapeutic effect maintains the patient's health.

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

[0121] To identify patients who may be potential responders to the treatment according to the invention, patients can also be selected by evaluating the recovery of heart rate after standing. To perform this test, the patient lies quietly in a supine position for 10 minutes before the orthostatic test. Supine position means lying horizontally with face and torso facing up. In this supine position, baseline values ​​of heart rate, systolic blood pressure and diastolic blood pressure are recorded. The patient then stands up quickly (<5 seconds). After standing up, heart rate, systolic blood pressure and diastolic blood pressure are recorded for 1 minute with a 10 second interval. The difference from the baseline value is calculated by subtracting the baseline value (heart rate value measured while lying on the back) from the heart rate value measured at each time point during standing. In patients with heart failure whose heart rate difference between 10 seconds after standing up and 20 seconds after standing up (heart rate recovery, i.e., the difference from the peak heart rate immediately after standing up) is less than 6 beats per minute, neuromodulation methods that stimulate the sensory nerve innervation of the tragus can be expected to lower hypertension, improve left ventricular hypertrophy, and improve cardiac function.

[0122] [Equipment parts] The device for adjusting cerebral blood flow to treat cardiovascular disease according to an embodiment includes at least one earpiece (preferably two earpiece pairs) with 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 shape of the electrical stimulation signal and the pattern of stimulation. The pair of electrodes includes a stimulation electrode and a reference electrode. The stimulation electrode is configured to provide an electrical stimulation signal to the tragus. The reference electrode is configured to allow an electrical current to flow across the tragus. The device may optionally include the following components: electrical circuitry and cardiovascular function sensors for measuring and monitoring the voltage and current of the provided signal and cardiovascular physiological signals (e.g., ECG, blood pressure, etc.), a microcontroller or computer, memory, a user input keyboard, peripherals, physiological sensors, display elements, circuitry for inputting, controlling, and recording data regarding the use of the device, external devices that can program the device or transmit data and information to (from) the device, wireless / wired communication systems for interfacing with a computer, tablet, or smartphone, etc. In this manner, it is expected that a patient receiving treatment with a device including stimulation of the sensory innervation of the tragus according to the present invention will have improved cerebral blood flow, reduced arterial blood pressure and left ventricular hypertrophy, improved cardiovascular function, etc. In a preferred embodiment, the device includes first and second earpieces, and stimulation of the sensory innervation of the tragus is performed at both tragus.

[0123] FIG. 6 is a block diagram of the device according to the present invention. The signal generator 10 comprises a signal / waveform generating section 4, a controller 5, a memory 17, an auxiliary circuit 3, a user data input / control device 16 (e.g., keypad, dial, actuator / switch, etc.), a display device 15, and a communication module (wireless / wired communication) 6. The illustrated signal generator 10 comprises a transmitter or communication module or other input / output circuit (i / o port) 12. By means of the i / o port 12, the signal generating device 10 can communicate with other devices 8. Thus, for example, the signal generating device 10 can be programmed or historical generated data recorded over time can be uploaded. The i / o port 12 may include a switch (e.g., a mechanical switch, an electric 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 provides stimulation signals (determined by the stimulation program) using a defined schedule to regulate the user's cerebral blood flow, lower arterial blood pressure, reduce left ventricular hypertrophy, or reduce AF load and improve cardiovascular function. In various embodiments, the device further comprises at least one port 12, which is part of the controller 4 or microcontroller 5, for connecting at least one lead 13 (FIG. 6). In this manner, the lead 13 can be removed from the signal generator 10 and other leads can be used with the signal generator 10. The lead 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 stimulation signal. More specifically, the signal generator 10 may be for determining time course parameters (e.g., pulse width, pulse frequency, waveform, waveform pattern, etc.) related to the stimulation algorithm. Examples of waveform patterns include, but are not limited to, sine waves, square waves, triangle waves, biphasic symmetric waves, biphasic asymmetric waves, and "white noise" signals. FIG. 7B shows some examples of stimulation waveforms that can be used to transcutaneously stimulate the sensory innervation of the tragus. The controller preferably generates the electrical parameters (current or voltage strength, frequency, burst frequency, waveform and duration, also referred to as waveform parameters) of the stimulation algorithm 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 sensor. This determination may be performed in three ways. First, it is performed by user control using the display 15 or input / control device 16. Second, it is performed automatically by pre-programmed computer readable instructions determined by the microcontroller. Third, it is performed by programmed computer readable instructions determined by the external computer 8.

[0125] The controller 4, microcontroller 5, memory 17, auxiliary circuits 3, user input / control devices 16 (e.g. keypad, dials, switches, etc.), display device 15, communication module (wireless or wired communication) 6 may be located in the same component, which may be a portable battery powered electronic device. The portable electronic device is preferably capable of running applications (or Apps) and is preferably a laptop computer, tablet or 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 auxiliary circuitry 3 for providing an electrical stimulation signal to at least one electrode pair 1, 2 to stimulate at least one tragus (preferably both tragus) of a human ear when appropriate signals are applied to the electrodes.

[0127] The stimulation algorithm is applied using a single lead and a single electrode on that lead. However, multiple leads and multiple electrodes on that lead may be used. The electrodes 1, 2 may be of a wearable device and are preferably connected to the signal generator 10 via an electrical cable 14 or a wireless connection such as Bluetooth. In embodiments where multiple 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 in pattern or waveform parameters.

[0128] The signal generator may be an open loop or closed loop system and may be controlled by computer readable instructions. In closed loop embodiments, a stimulation algorithm may be applied in response to a signal from a cardiovascular parameter sensor 7, which may include one or more of the following sensors: blood pressure sensor, temperature sensor, pulse oximeter, electrocardiogram sensor, heart rate sensor, temperature and tissue impedance sensor. These sensors use electrodes connected to the body to sense parameters or monitor / measure cardiovascular function. A stimulation algorithm is applied that continuously reduces blood pressure using the sensed parameters. In this way, a closed loop system may use information from the cardiovascular sensor as a feedback mechanism or program to reduce or increase stimulation intensity, modify or change waveforms or waveform parameters to keep the physiological parameters measured during stimulation at appropriate values ​​below upper and above lower limits. In open loop embodiments, an external device 8 is used to apply a stimulation algorithm that continuously reduces blood pressure or adjusts waveform parameters. In some embodiments, the signal generator is also used to set parameters of the stimulation signal. In some embodiments, the signal generator is used to vary the parameters of the stimulation algorithm using the user data input device 16 or external computer 8 to adjust the intensity of the stimulation.

[0129] The memory 11 (or memory portion) contains computer readable instructions that can be operated by a controller or microcontroller to perform the functions of the device. Thus, in some embodiments, the signal generator can be used to execute the instructions to provide electrical stimulation signals based on preprogrammed stimulation algorithms to treat conditions such as hypertension, heart failure, left ventricular hypertrophy, and atrial fibrillation. Additionally, in some embodiments, the signal generator is used to set stimulation signal parameters. In some embodiments, the signal generator is used to vary parameters of the stimulation signal to adjust the strength of the electrical stimulation signal. These are shown in FIG. 7A as stimulation strength.

[0130] The microcontroller and memory device may contain pre-programmed computer readable instructions to provide controlled electrical access to the signal generator, execution security, password or encryption features to restrict access to the device and stored data / information (e.g., user and maintenance instructions, legal or statutory required device data, etc.).

[0131] In some embodiments, one or more physiological parameters of the patient may be measured and recorded by the device using a sensor, such as a cardiovascular sensor. Furthermore, some of these measurements may be taken at different times during a stimulation period or over multiple stimulation periods to establish a value or range of values ​​of the physiological parameter. In some embodiments, the voltage or current strength of the electrical stimulation signal and their phase relationship may be used to determine the electrical impedance of the patient's skin and recorded by the device. In this way, the values ​​or ranges of values ​​of these physiological parameters recorded in association with device use (date, time, waveform and waveform parameters) during the stimulation algorithm may be recorded and combined to form a data set representative of the patient's device use. In this way, information is provided and recorded regarding the patient's device usage. This information may also be reported to an external device. This information may then be used to monitor the patient's condition or to provide or provide evidence of the patient's compliance with the stimulation / treatment program (which may be defined by a physician, medical professional, or defined by a health care contract or insurance agreement with a third party). Furthermore, in some embodiments, the individual usage data set may be accessed remotely using the communication module. This allows for remote monitoring of the patient, checking patient compliance with the health management / treatment plan, applying initial and continuing courses of stimulation, and applying stimulation algorithms to modify the prescribed treatment plan.

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

[0133] In some embodiments, the individual usage data may be analyzed to determine whether the patient has used the device as prescribed by a physician or medical professional or whether the patient has complied with the terms of their health insurance policy, thereby determining whether penalties have been incurred, changes in premiums, changes in benefits or other coverage, etc.

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

[0135] [Pulse waveform] As shown in FIG. 7A, an electrical stimulation signal has an intensity, a waveform, a pulse width, and a frequency. Intensity is the strength or amplitude of the signal waveform in volts or amperes (the difference between the maximum and minimum of the waveform). Frequency is the number of times the waveform repeats per second, expressed in Hz. Pulse width is the length of time from the start to the end of the waveform itself, expressed in seconds. A square wave is shown in FIG. 7A. Some examples of stimulation pulse waveforms that can be used for percutaneous tragus sensory innervation stimulation are shown in FIG. 7B. The waveforms may be of any shape, including, but not limited to, a sinusoidal square wave, a triangular wave, a biphasic wave, or a "white noise" waveform.

[0136] The generated waveform may be a symmetric monophasic wave, a symmetric biphasic wave, or a symmetric triphasic wave. The generated waveform may be an asymmetric monophasic wave, an asymmetric biphasic wave, or an asymmetric triphasic wave. The waveform may be any other shape.

[0137] In some embodiments, the electrical stimulation signal may include a cyclically repeating multi-phasic pulse waveform, where the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes positive relative to the signal at the reference electrode is greater than the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes negative relative to the signal at the reference electrode.

[0138] In this case, a net normal current is applied for the duration of the pulse such that the stimulating electrode is positive with respect to the reference electrode.

[0139] In some embodiments, the electrical stimulation signal may include a cyclically repeating multi-phasic pulse waveform, where the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes positive relative to the signal at the reference electrode is less than the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes negative relative to the signal at the reference electrode.

[0140] In this case, a net normal current is applied for the duration of the pulse such that the stimulating electrode is negative with respect to the reference electrode.

[0141] In some embodiments, the multi-phasic pulse waveform is a biphasic pulse waveform. In some embodiments, the multi-phasic pulse waveform is a triphasic pulse waveform.

[0142] In some embodiments, the electrical stimulation signal may include a cyclically repeating pulse waveform including a plurality of pulses, where the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes positive relative to the signal at the reference electrode is greater than the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes negative relative to the signal at the reference electrode.

[0143] In this case, a net normal current is applied for 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 cyclically repeating pulse waveform including a plurality of pulses, where the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes positive relative to the signal at the reference electrode is less than the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes negative relative to the signal at the reference electrode.

[0145] In this case, a net normal current is applied for 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-invasive electrical stimulation of nerves projecting to the outer ear using the aforementioned device. The method includes attaching a stimulating electrode and a reference electrode to contact the tragus of a user, generating an electrical stimulation signal applied to the stimulating electrode and the reference electrode using the aforementioned device, and determining a waveform and frequency of the electrical stimulation signal using a controller. The electrical stimulation signal includes a train of 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 pulse frequency, pulse duration and intensity are selected to be in the ranges disclosed herein.

[0148] In some embodiments, the method includes applying an electrical stimulation signal to the user's tragus, such that the current between the stimulation electrode and the reference electrode flows primarily through tissue of the tragus, with negligible current flowing through tissue that does not form the tragus.

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

[0150] In some embodiments, the electrical stimulation signal comprises a cyclically repeating train of pulses selected such that during each cycle a net normal current flows from the stimulation electrode to the reference electrode.

[0151] In some embodiments, the electrical stimulation signal is selected such that a net normal current flows from the stimulation electrode to the reference electrode during the entire duration of the cyclically repeating succession of pulses.

[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 comprises a cyclically repeating multi-phasic pulse waveform, where the pulse magnitude or phase duration when the signal at the stimulating electrode goes positive relative to the signal at the reference electrode is greater than the pulse magnitude or phase duration when the signal at the stimulating electrode goes negative relative to the signal at the reference electrode, and where a net normal current is delivered during the duration of the pulse when the stimulating electrode is positive relative to the reference electrode.

[0154] In some embodiments, the electrical stimulation signal comprises a cyclically repeating multi-phasic pulse waveform, where the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes positive relative to the signal at the reference electrode is less than the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes negative relative to the signal at the reference electrode.

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

[0156] In some embodiments, the multi-phasic pulse waveform is a biphasic pulse waveform. In some embodiments, the multi-phasic pulse waveform is a triphasic pulse waveform.

[0157] In some embodiments, the electrical stimulation signal comprises a cyclically repeating pulse waveform including a plurality of pulses, where the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes positive relative to the signal at the reference electrode is greater than the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes negative relative to the signal at the reference electrode, and where a net normal current is delivered during the duration of the pulse when the stimulating electrode goes positive relative to the reference electrode.

[0158] In some embodiments, the electrical stimulation signal comprises a cyclically repeating pulse waveform comprising a plurality of pulses, where the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes positive relative to the signal at the reference electrode is less than the magnitude or phase duration of the pulse when the signal at the stimulating electrode goes negative relative to the signal at the reference electrode.

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

[0160] [Optimized treatment program (example)] It has been found that, in order to achieve the effect exerted as a sustained reduction in arterial blood pressure in hypertensive patients, an improvement in cardiac function in heart failure or a reduction in AF load, electrical stimulation of the sensory innervation of the tragus requires the use of current pulses with specific parameters: frequency 1-30 Hz, intensity 0.1-8 mA, pulse width 10-250 microseconds. It is preferable to stimulate both tragus sides, i.e. the left and right tragus simultaneously, with square monophasic or biphasic symmetrical or asymmetrical pulses. The experimental results shown in Figure 2 show that the therapeutic effect is related to and is the result of the improvement of cerebral blood flow. In particular, the therapeutic effect is exerted by using a frequency of 1 Hz to 10 Hz. Furthermore, the therapeutic effect is also exerted by using a frequency of 3 Hz to 50 Hz. Furthermore, the therapeutic effect is more pronounced by using a pulse width of 10 microseconds to 500 microseconds and an intensity of 0.1 mA to 8 mA. The therapeutic effect is also exerted by using a pulse width of 100 microseconds to 500 microseconds. In some embodiments of the method, only one of the stimulation parameters (frequency, intensity, pulse width) needs to be optimized; therefore, not all parameters need to be optimized to produce a therapeutic effect. For example, in one embodiment, the electrical stimulation signal may include pulses repeating at a frequency between 1 Hz and 100 Hz, with each pulse having a duration between 10 microseconds and 500 microseconds, or an intensity between 0.1 mA and 20 mA.

[0161] For completeness, it is noted that in one embodiment, the electrical stimulation signal comprises a train of electrical pulses, each pulse repeated at a frequency range of about 3 Hz to about 50 Hz, each pulse having a duration of about 100 microseconds to about 500 microseconds and an intensity of about 0.1 mA to about 8 mA.

[0162] In some embodiments, the frequency is in the range of about 1 Hz to about 100 Hz, e.g., 1 Hz to 10 Hz, 10 Hz to 20 Hz, 20 Hz to 30 Hz, 30 Hz to 40 Hz, 40 Hz to 50 Hz, 50 Hz to 60 Hz, 60 Hz to 70 Hz, 70 Hz to 80 Hz, 80 Hz to 90 Hz, or 90 Hz to 100 Hz.

[0163] In some embodiments, the frequency is in the range of 3 Hz to 20 Hz, 5 Hz to 30 Hz, 10 Hz to 50 Hz, 15 Hz to 60 Hz, 20 Hz to 75 Hz, 25 Hz to 80 Hz, or 30 Hz to 100 Hz.

[0164] In some embodiments, the frequency is in the range of 3 Hz to 500 Hz, inclusive. In some embodiments, the frequency is in the range of about 3 Hz to about 35 Hz, inclusive.

[0165] In some embodiments, the pulse duration is in the range of about 10 ms to about 500 ms, e.g., 10 ms to 100 ms, 20 ms to 200 ms, 30 ms to 300 ms, 40 ms to 400 ms, or 50 ms to 500 ms.

[0166] In some embodiments, the pulse duration is in the range of from 100 to 200 ms, from 200 to 300 ms, from 300 to 400 ms, or from 400 to 500 ms.

[0167] In some embodiments, the pulse duration is in the range of from 50 to 200 ms, from 100 to 250 ms, or from 200 to 500 ms.

[0168] In some embodiments, the pulse duration is in the range of 100 to 500 ms, inclusive. In some embodiments, the pulse duration is in the range of 100 to 300 ms, inclusive.

[0169] In some embodiments, the intensity is in the range of about 0.1 mAsec to about 10 mA, e.g., about 0.1 mAsec to about 2 mA, about 0.2 mAsec to about 5 mA, or about 0.5 mAsec to about 10 mA.

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

[0171] In some embodiments, the intensity is in the range of 0.1 mAsec to 5 mA, 0.5 mAsec to 8 mA, or 1 mAsec to 10 mA.

[0172] In some embodiments, the intensity is in the range of about 0.5 mAsec to about 5 mAsec.

[0173] In some embodiments, the intensity is in the range of about 0.1 mAsec to about 20 mA.

[0174] In order to achieve cerebral blood flow regulation aimed at improving the hypertensive condition or left ventricular hypertrophy in hypertensive patients, neuromodulation by electrical stimulation of the sensory innervation of the tragus requires continuous treatment. This treatment includes multiple stimulation sessions according to the following stimulation treatment program: stimulation is given simultaneously to the left and right tragus (i.e., bilaterally) every day; the duration of stimulation is not less than 5 minutes and not more than 2 hours per day, for at least three consecutive days (initial course of treatment); the therapeutic effect can be optimized by applying this electrical tragus stimulation method to the user for a minimum of 5 minutes and a maximum of 2 hours per day; electrical stimulation is given to the user with an interval of at least one day. Thereafter, stimulation may be given simultaneously to the left and right tragus once a week (once every 7 days). The duration of stimulation is a maximum of 2 hours per session (continuous course of treatment).

[0175] A further treatment regimen shown to be effective involves providing sensory innervation electrical stimulation to the user's tragus using different durations. During a first duration, the method is applied to the user for at least 5 minutes and up to 2 hours per day. Typically, the first duration lasts a minimum of 3 days. However, the number of days the stimulation is provided may be longer depending on the needs of the user to achieve a therapeutic effect. During a second duration, the method is discontinued for at least 2 days. During a third duration, the method is applied to the user for at least 5 minutes and up to 2 hours per day.

[0176] The use of the therapeutic device and method of the present invention may be administered to the user in combination with any pharmaceutical treatment in accordance with clinical guidelines for pharmaceutical effect regulation.

[0177] Further, in one embodiment of the method, the user's therapy algorithm is adjusted in response to the blood pressure measurement. The therapy may include continuous measurement of the patient's blood pressure. This measurement may then be compared to a predefined 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 communications module. First, the user's blood pressure is measured and recorded in a memory portion of the device. The controller then determines whether the user's blood pressure is above the predefined threshold. If the user's blood pressure is above the predefined threshold, a command is sent to a signal generator to generate an electrical stimulation signal.

[0178] The only officially accepted treatment for hypertension today is medication. However, this may not be effective for some patients. Another major challenge with pharmaceutical therapy is that hypertension is a lifelong condition, so patients must continue to take medication for the rest of their lives. Many patients (45% of those receiving treatment) do not take their prescribed medication. This is partly due to side effects and lack of enthusiasm. The technical advantage of the claimed device-based treatment is that the treatment is effective for patients who are drug resistant or cannot be managed with medication. The claimed treatment also allows the patient to be treated for a short period of time or to have a device implanted. The treatment is effective even if the patient does not perform any activities for a long time or does not take medication regularly. In the examples of the present disclosure, the treatment including stimulation of the tragus sensory innervation can be applied to the patient for 3 days to 2 weeks. In this case, in some patients, the blood pressure remained lowered for several weeks after the first course of treatment. In other patients, the blood pressure remained lowered for up to 12 months after the first course of treatment. The treatment can then be repeated. The claimed treatments may also be used in combination with prescribed medications.

[0179] Another advantage of the claimed device based therapy is that it allows verification of device usage. This allows medical professionals to monitor the patient's use of the device and compliance with the prescribed therapy. This monitoring can be done remotely. The only way to do this with drugs is through blood / urine tests, which are time consuming and expensive. Continuing the correct treatment is a big challenge for health insurance and public health funds, because maintaining blood pressure within the recommended range significantly reduces the risk of stroke, myocardial infarction, kidney failure, dementia, etc., and significantly reduces lifetime health and social care costs.

[0180] The features of the above aspects may be combined in any suitable manner. The above description of specific embodiments is given by way of example only. Those skilled in the art will appreciate that many modifications and variations are possible. It will be appreciated that such modifications and variations are within the scope of the invention as defined in the claims.

Claims

1. A device for regulating cerebral blood flow 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. the stimulation electrodes are configured to provide the electrical stimulation signal to the user transcutaneously or transdermally; or 10. The device of claim 1, wherein the stimulation electrodes are configured to deliver the electrical stimulation signal transcutaneously to the user.

3. a second earpiece including a second electrode and a second reference electrode; 3. The device of claim 1 or 2, wherein the second earpiece is positioned to contact the tragus of the opposite ear of the user.

4. 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; 4. The apparatus according to claim 1, wherein the reference electrode is selectively disposed in the second gripping portion.

5. 5. 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.

6. 6. The apparatus of claim 5, wherein the values ​​stored in the memory unit are used by the controller to determine the shape of the electrical stimulation signal.

7. 7. The device according to claim 5 or 6, wherein the physiological sensor is located on the earpiece.

8. 8. An apparatus according to any one of claims 5 to 7, 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 apparatus.

9. 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; 9. The device of claim 8, wherein information regarding the electrical impedance of the tragus and the time and date of use is optionally stored in said memory portion.

10. the controller is configured to generate the electrical stimulation signal and a pattern of stimulation based on user input received at the controller; 10. The apparatus of claim 9, 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.

11. the electrical stimulation signal is a pulse waveform comprising a continuous substantially square wave; 11. The apparatus of 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.

12. A system for regulating cerebral blood flow in a user, comprising: A device according to any one of claims 1 to 11, 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.

13. An apparatus according to any one of claims 1 to 11, 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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