CN116917003A

CN116917003A - Monitoring and treating atrial fibrillation, arrhythmia, and additional conditions

Info

Publication number: CN116917003A
Application number: CN202280018151.2A
Authority: CN
Inventors: A·齐夫; Y·霍兰德
Original assignee: Ziff Medical Co
Current assignee: Ziff Medical Co
Priority date: 2021-01-18
Filing date: 2022-01-18
Publication date: 2023-10-20

Abstract

A system comprising: a control module; a neural stimulation unit operatively controlled by the control module and configured to generate an electrical stimulation signal having a frequency between 40-50 Hz; and at least two electrodes configured to be positioned in simultaneous transdermal contact with an inner surface of a wrist of the subject and proximate to a median nerve of the subject, wherein each of the at least two electrodes is connected to the neural stimulation unit for delivering the generated electrical stimulation signals from the neural stimulation unit to the subject, wherein the electrical stimulation signals are configured to apply neuromodulation therapy to the subject to reduce the occurrence of a central arrhythmia-related condition in the subject.

Description

Monitoring and treating atrial fibrillation, arrhythmia, and additional conditions

Cross Reference to Related Applications

The present application claims priority from U.S. provisional patent application No. 63/138561, entitled "MONITORING and treating atrial fibrillation, arrhythmia, and additional conditions (monitor AND TREATING ATRIAL FIBRILLATION, ARRYTHMIA, AND ADDITIONAL CONDITIONS)" filed on month 1, month 18 of 2021, and U.S. provisional application No. 63/210570, entitled "MONITORING and treating atrial fibrillation, arrhythmia, and additional conditions (monitor AND TREATING ATRIAL FIBRILLATION, ARRYTHMIA, AND ADDITIONAL CONDITIONS)" filed on month 6, 2021, the contents of both of which are incorporated herein by reference in their entirety.

Technical Field

Some applications of the present invention generally relate to devices and methods for monitoring and treating arrhythmia-related events.

Background

Neuromodulation is used to treat a variety of conditions, ranging from mental conditions (such as depression) to physiological conditions (such as chronic pain). In particular, neuromodulation of peripheral nerves may be used to modulate the autonomic nervous system.

Portable devices for monitoring and treating various physiological conditions allow real-time treatment, whether in response to an acute crisis or impact on the overall health status and improving mood. In recent years, the number of consumer wearable devices designed to monitor physiological conditions has increased dramatically, from devices designed to track vital signs such as heart rate or blood pressure, to recreational wearable devices such as wearable fitness trackers.

The foregoing examples of the related art and limitations related thereto are intended to be illustrative rather than exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.

Disclosure of Invention

The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools, and methods which are meant to be exemplary and illustrative, not limiting in scope.

In one embodiment, a system is provided, comprising: a control module; a neural stimulation unit operatively controlled by the control module and configured to generate an electrical stimulation signal having a frequency between 40-50 Hz; and at least two electrodes configured to be positioned in simultaneous transdermal contact with an inner surface of a wrist of the subject and proximate to a median nerve of the subject, wherein each of the at least two electrodes is connected to the neural stimulation unit for delivering the generated electrical stimulation signals from the neural stimulation unit to the subject, wherein the electrical stimulation signals are configured to apply neuromodulation therapy to the subject to reduce the occurrence of a central arrhythmia-related condition in the subject.

In one embodiment, there is also provided a method comprising: there is provided a system comprising a control module, a neural stimulation unit operably controlled by the control module and configured to generate an electrical stimulation signal having a frequency between 40-50Hz, and at least two electrodes configured to be positioned in simultaneous transdermal contact with an inner surface of a wrist of a subject and in proximity to a median nerve of the subject, wherein each of the at least two electrodes is connected to the neural stimulation unit for delivering the generated electrical stimulation signal from the neural stimulation unit to the subject, wherein the electrical stimulation signal is configured to apply neuromodulation therapy to the subject to reduce the occurrence of a arrhythmia-related condition in the subject; and placing the at least two electrodes in simultaneous transdermal contact with the inner surface of the wrist of the subject such that each of the at least two electrodes is positioned adjacent and substantially parallel to the longitudinal axis of the median nerve along its longitudinal axis.

In some embodiments, the control module is configured to operate the neural stimulation unit to generate the electrical stimulation signal according to a predetermined schedule, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes.

In some embodiments, the control module is configured to receive as input data indicative of at least one parameter selected from the group of parameters consisting of: an activity state parameter of the subject, a diet state parameter of the subject, and an emotional state parameter of the subject.

In some embodiments, the control module is configured to predict a current or impending occurrence of an arrhythmia-related condition about the subject based on the data, and operate the neural stimulation unit to generate an electrical stimulation signal based at least in part on the prediction, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes.

In some embodiments, the activity state parameter of the subject indicates that the subject is at least one of: eating, lying down, sleeping, walking, running, exercising or driving; the dietary status parameter of the subject indicates that the subject is at least one of: starvation, eating or recently eating; the emotional state parameter of the subject indicates that the subject is at least one of: tension, relaxation, emotional aggression, depression, anxiety, or mental trauma.

In some embodiments, the control module is further configured to receive as additional input data indicative of at least one additional parameter about the subject, the at least one additional parameter selected from the group consisting of: fatigue, chest distress, palpitations, dizziness, fainting, headache, shortness of breath, chest "empty" sensations, tachycardia or tremors, heart jump (skipping heart beats), throat pressure, cold or chills, dehydration, blood related parameters, anemia diagnosis, digestive related symptoms, insomnia and hormonal data.

In some embodiments, the predicting is based at least in part on correlating at least one of the parameters comprising the data in the subject with the occurrence of the arrhythmia-related condition, wherein the correlating is based on current and historical information associated with the occurrence of the arrhythmia-related condition in the subject.

In some embodiments, the control module is further configured to receive a cardiac activity signal of the subject as an additional input.

In some embodiments, the control module is further configured to process the cardiac activity signal to derive one or more cardiac activity related parameters selected from the group consisting of: heart Rate Variability (HRV), heart rate recovery, heart rate reserve, atrial extra-systole (PAC), ventricular extra-systole, atrial tachycardia, RR intervals, average interval between normal heartbeats (AVNN), standard deviation of NN intervals (SDNN), root mean square of continuous differences between normal heartbeats (rMSSD), pNN50, low frequency activity (LF), and high frequency activity (HF).

In some embodiments, the control module is further configured to detect a current or impending occurrence of an arrhythmia-related condition regarding the subject based on the cardiac activity signal, and operate the neural stimulation unit to generate an electrical stimulation signal based at least in part on the detection, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes.

In some embodiments, the control module is further configured to determine that the autonomic nervous system of the subject is in a sympathetic state or a parasympathetic state.

In some embodiments, when the subject's autonomic nervous system is in a sympathetic nervous state, the control module is configured to operate the neural stimulation unit to generate the electrical stimulation signal at a frequency between 1-5 Hz.

In some embodiments, the system further comprises at least one of: electrocardiograph (ECG) sensors, photoplethysmogram (PPG) sensors, and accelerometers.

In some embodiments, the system is at least partially housed within a wearable device configured to be worn by a subject.

In some embodiments, the wearable device includes a wristband configured to be worn around a wrist of the subject such that the at least two electrodes are each positioned along their longitudinal axis proximate to and substantially parallel to the longitudinal axis of the median nerve.

In some embodiments, the arrhythmia-related condition is one or more of: atrial Fibrillation (AF), atrial premature beat complex (PAC), ventricular premature beat complex (PVC), supraventricular tachycardia (SVT), atrial Tachycardia (AT), atrial flutter, atrioventricular node reentry tachycardia (AVNRT), paroxysmal supraventricular tachycardia (PSVT), atrioventricular reentry tachycardia, pre-excitation syndrome, ventricular Tachycardia (VT), torsades de pointes (TdP), long QT syndrome, cardiac arrest and sick sinus syndrome.

In some embodiments, the control module is further configured to measure a current associated with the electrical stimulation signal between the at least two electrodes, and determine that the positioning of the at least two electrodes relative to the inner surface of the wrist of the subject is incorrect when the measured current is below a predetermined baseline value.

In some embodiments, when each of the at least two electrodes is positioned adjacent along its longitudinal axis and substantially parallel to the longitudinal axis of the median nerve, the predetermined baseline value is determined by measuring the current associated with the electrical stimulation signal between the at least two electrodes.

In one embodiment, there is further provided a system comprising a control module; a neural stimulation unit operably controlled by the control module and configured to generate an electrical stimulation signal; and at least two electrodes configured to be positioned in simultaneous transdermal contact with an inner surface of a wrist of the subject and proximate to a median nerve of the subject, wherein each of the at least two electrodes is connected to the neural stimulation unit for delivering the generated electrical stimulation signals from the neural stimulation unit to the subject, wherein the control module is configured to: receiving as input a cardiac activity signal of a subject; detecting a current or impending arrhythmia-related condition regarding the subject based on the cardiac activity signal; and operating the neural stimulation unit to generate an electrical stimulation signal having a frequency between 40-50Hz, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via at least two electrodes, and wherein the electrical stimulation signal is configured to apply a neuromodulation therapy to the subject to reduce the occurrence of arrhythmia-related conditions in the subject.

In one embodiment, there is also provided a method comprising: providing a system comprising a control module; a neural stimulation unit operatively controlled by the control module and configured to generate an electrical stimulation signal; and at least two electrodes configured to be positioned in simultaneous transdermal contact with an inner surface of a wrist of the subject and proximate to a median nerve of the subject, wherein each of the at least two electrodes is connected to the neural stimulation unit for delivering the generated electrical stimulation signals from the neural stimulation unit to the subject, wherein the control module is configured to: receiving as input a cardiac activity signal of a subject; detecting a current or impending occurrence of an arrhythmia-related condition with respect to the subject based on the cardiac activity signal, and operating the neural stimulation unit to generate an electrical stimulation signal having a frequency between 40-50Hz, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via at least two electrodes, and wherein the electrical stimulation signal is configured to apply a neuromodulation therapy to the subject to reduce the occurrence of the arrhythmia-related condition in the subject; and placing the at least two electrodes in simultaneous transdermal contact with the inner surface of the wrist of the subject such that each of the at least two electrodes is positioned adjacent and substantially parallel to the longitudinal axis of the median nerve along its longitudinal axis.

In some embodiments, the control module is configured to detect an impending arrhythmia-related condition based at least in part on detecting at least one of atrial premature composite (PAC) and ventricular premature composite (PVC) in the cardiac activity signal.

In some embodiments, the detection is based on measuring a percentage increase in one of PAC and PVC in the cardiac signal relative to a baseline measurement of the subject.

In some embodiments, the detection is based at least in part on one or more cardiac activity related parameters.

In some embodiments, the control module is further configured to receive as additional input data indicative of at least one additional parameter selected from the group consisting of: the activity state of the subject, the diet state of the subject, and the emotional state of the subject.

In some embodiments, the system is housed within a wearable device configured to be worn by a subject, wherein the wearable device comprises a wristband configured to be worn around a wrist of the subject such that the at least two electrodes are each positioned along their longitudinal axis proximate and substantially parallel to the longitudinal axis of the median nerve.

In some embodiments, the predetermined baseline value is determined by measuring a current associated with the electrical stimulation signal between the at least two electrodes when each of the at least two electrical stimulation signals is positioned along its longitudinal axis proximate to and substantially parallel to the longitudinal axis of the median nerve.

According to some applications of the present invention, the wearable device is configured to be placed on a wrist of a subject in a predetermined configuration. At least some of the electrodes are wrist-facing electrodes configured to be placed in contact with skin of a subject's wrist. The wrist-facing electrode is typically arranged such that when the wrist-wearable device is placed on the wrist of a subject in a predetermined setting, the wrist-facing electrode is disposed near the ulnar nerve and/or median nerve of the subject. For example, the device may be configured such that when the device is placed on the subject's wrist with the screen facing up, the wrist-facing electrode is disposed near the subject's ulnar nerve and/or median nerve.

Notably, although some sensing and/or neuromodulation techniques and algorithms for use therewith are described herein with reference to a wearable device, the scope of the present invention includes practicing any of the sensing and/or neuromodulation techniques and algorithms for use therewith without using a wearable device. For example, such techniques and algorithms may be practiced without a wearable device using electrodes and/or sensors placed in contact with the subject's body, and/or using a wearable device worn on a portion of the subject's body other than the subject's wrist. In some embodiments, one or more of the ulnar nerve, median nerve, radial nerve, tibial nerve, fibular nerve, subcostal nerve, intraspinal nerve, and/or different nerves of the subject are stimulated.

In some embodiments, the device is configured to provide neuromodulation therapy by delivering an electrical signal from a first one of the wrist-facing electrodes to another one of the wrist-facing electrodes such that the electrical signal passes through the ulnar nerve and/or median nerve of the subject. Typically, the device is configured to provide neuromodulation therapy, such as the occurrence of atrial premature contractions, ventricular premature contractions, supraventricular tachycardia, and/or atrial tachycardia, to a subject experiencing Atrial Fibrillation (AF) and/or arrhythmia disease (in some embodiments, the directionality of the signal alternates between the electrodes). The signal typically has any one of a sinusoidal waveform, a triangular waveform, a rectangular waveform and/or a sawtooth waveform. Typically, during a given treatment session, the signal is applied at a switching duty cycle, wherein the signal is applied for 5 to 30 seconds and then turned off for a period of 0 to 5 seconds.

The signal is typically driven at a frequency of 40-50Hz (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 Hz). As demonstrated by the data provided herein, such stimulation parameters have been found to generally reduce the occurrence of AF and/or arrhythmic diseases (indicative of an improvement in cardiovascular distress and/or a reduction in cardiovascular exacerbations). The inventors have also found that stimulating certain subjects at a frequency between 1-5Hz (e.g., 1, 2, 3, 4, or 5 Hz) can reduce the occurrence of AF and/or arrhythmic diseases (indicative of an improvement in cardiovascular distress and/or a reduction in cardiovascular exacerbations). Thus, in some embodiments, the signal is driven at a frequency between 1-5Hz (e.g., 1, 2, 3, 4, or 5 Hz). In some embodiments, the system selects which signal parameters to apply to the subject during a given treatment based on one or more detected parameters and/or additional inputs.

Thus, according to some applications of the present invention, there is provided an apparatus comprising: a wearable device configured to be worn by a subject, the wearable device comprising one or more electrodes, and the wearable device configured to detect a heart related parameter of the subject; and at least one computer processor associated with the wearable device, the computer processor configured to: receiving a detected heart related parameter of the subject; detecting an increase in the incidence of premature atrial contraction and/or atrial tachycardia in the subject based on the detected heart related parameter; in response, at least in part, one or more electrodes of the wearable device are driven to apply an electrical stimulation therapy to the subject, the electrical stimulation therapy having a frequency selected from the group consisting of between 40Hz and 50Hz and between 1Hz and 5 Hz.

In some applications, the wearable device includes a wristband, and at least one of the one or more electrodes is configured to be placed near the median nerve and/or ulnar nerve of the subject when the wristband is worn in a predetermined setting.

In some applications, the wearable device includes a PPG sensor, and the wearable device is configured to detect a heart related parameter of the subject by utilizing the PPG sensor.

In some applications, the wearable device includes an accelerometer, and the wearable device is configured to detect a heart related parameter of the subject by utilizing the accelerometer.

In some applications, the computer processor is additionally configured to receive an input indicative of at least one additional parameter selected from the group consisting of: the method includes the steps of determining an activity state of the subject, a dietary state of the subject, an emotional state of the subject, and a time of day, and driving one or more electrodes to apply an electrical stimulation therapy to the subject in response to at least one additional parameter in combination with a detected increase in the incidence of premature atrial contractions and/or atrial tachycardia of the subject.

In some applications, the computer processor is further configured to determine that the subject is in a parasympathetic state, and the computer processor is configured to, in response to detecting that the subject is in the parasympathetic state, in conjunction with the detected increase in the incidence of premature atrial contractions and/or atrial tachycardia of the subject, drive one or more electrodes of the wearable device to apply an electrical stimulation therapy to the subject having a frequency between 40Hz and 50 Hz.

In some applications, the computer processor is further configured to determine that the subject is in a sympathological state, and in response to determining that the subject is in a sympathological state in combination with detecting an increase in the incidence of premature atrial contraction and/or atrial tachycardia of the subject, the computer processor is configured to drive one or more electrodes of the wearable device to apply an electrical stimulation therapy to the subject having a frequency between 1Hz and 5 Hz.

In some applications, the wearable device is configured to detect heart related parameters by recording the ECG of the subject with the electrodes.

In some applications, at least one of the electrodes is a dual function electrode configured to have a sensing mode in which the dual function electrode is configured to record an ECG of the subject and to have a stimulation mode in which the computer processor is configured to apply electrical stimulation therapy to the subject via the dual function electrode.

According to some applications of the present invention there is also provided a method comprising: detecting a heart related parameter of the subject using a wearable device comprising one or more electrodes; and using at least one computer processor: receiving the detected heart related parameter; detecting an increase in the incidence of premature atrial contraction and/or atrial tachycardia in the subject based on the detected heart related parameter; and in response thereto, at least in part, driving one or more electrodes of the wearable device to apply an electrical stimulation therapy to the subject, the electrical stimulation therapy having a frequency range selected from the group consisting of: between 40Hz and 50Hz, and between 1Hz and 5 Hz.

According to some applications of the present invention there is also provided an apparatus comprising: a wearable device configured to be worn by a subject and to receive input indicating that an episode of the subject has occurred; and at least one computer processor associated with the wearable device, the computer processor configured to: the impending AF is predicted at least in part in response to an input indicating that an episode has occurred, and an output is generated in response thereto.

According to some applications of the present invention there is also provided an apparatus comprising: a wearable device configured to be worn by a subject, the wearable device comprising one or more electrodes, and the wearable device configured to detect a heart related parameter of the subject; and at least one computer processor associated with the wearable device, the computer processor configured to: receiving the detected heart related parameter; detecting that the subject is experiencing AF in response to the detected heart related parameter; classifying the AF into a given category of AF; selecting an electrical stimulation therapy to be applied to the subject based on the category of AF; and driving one or more electrodes of the wearable device to apply the selected electrical stimulation therapy to the subject.

In some applications, the computer processor is configured to detect the onset of premature atrial contraction and/or atrial tachycardia in the subject that occurs prior to the AF, analyze the subject for the onset of premature atrial contraction and/or atrial tachycardia, and classify the AF as a given category of AF at least partially responsive thereto.

In some applications, the at least one computer processor is further configured to receive an input indicative of at least one additional parameter selected from the group consisting of: the method includes classifying AF into a given category of AF based at least in part on at least one additional parameter.

In some applications, the computer processor is configured to classify the AF into a given category of AF by classifying the AF as being interrelated with the parasympathetic state of the subject or the sympathetic state of the subject.

In some applications, in response to classifying the AF as being correlated to a parasympathetic state of the subject, the computer processor is configured to select to apply an electrical stimulation therapy to the subject having a frequency between 40Hz and 50 Hz.

In some applications, in response to classifying the AF as being correlated to a sympathetic state of the subject, the computer processor is configured to select to apply an electrical stimulation therapy to the subject with a frequency between 1Hz and 5 Hz.

In some applications, the computer processor is configured to analyze Heart Rate Variability (HRV) of the subject for a given period of time prior to the onset of the AF episode and classify the AF as being interrelated with parasympathetic status of the subject or sympathetic status of the subject based at least in part on the analysis of the HRV of the subject for the given period of time prior to the onset of the AF episode.

In some applications, the computer processor is configured to analyze the heart rate of the subject for a given period of time prior to the onset of the AF episode and classify the AF as being related to the subject parasympathetic state or the subject sympathetic state based at least in part on the analysis of the heart rate of the subject for the given period of time prior to the onset of the AF episode.

In some applications, the computer processor is configured to analyze heart rate recovery of the subject within a given time period prior to the onset of the AF episode and classify the AF as being interrelated with the subject parasympathetic or the subject sympathetic status based at least in part on the analysis of heart rate recovery of the subject within the given time period prior to the onset of the AF episode.

In some applications, the at least one computer processor is further configured to receive an input indicative of at least one additional parameter selected from the group consisting of: the method further includes classifying the AF as being interrelated with the parasympathetic state of the subject or the sympathetic state of the subject based at least in part on at least one additional parameter.

In some applications, the computer processor is configured to record the ECG of the subject using the electrodes, and classify the AF as being interrelated with the parasympathetic state of the subject or the sympathetic state of the subject based at least in part on analysis of the ECG.

In some applications, the computer processor is configured to classify the AF as being interrelated with a parasympathetic state of the subject or a sympathetic state of the subject based at least in part on the shape of the ECG signal.

In some applications, the computer processor is configured to classify the AF as being interrelated with the parasympathetic state of the subject or the sympathetic state of the subject based at least in part on the regularity of the beats in the ECG signal.

In some applications, at least one of the electrodes is a dual function electrode configured to have a sensing mode in which the electrode is configured to record the ECG of the subject and a stimulation mode in which the computer processor is configured to apply electrical stimulation therapy to the subject via the electrode.

According to some applications of the present invention there is also provided a method comprising: detecting a heart related parameter of the subject using a wearable device comprising one or more electrodes; and using at least one computer processor associated with the wearable device: receiving the detected heart related parameter; in response to the detected heart related parameter, detecting that the subject is experiencing AF; classifying the AF into a given category of AF; selecting an electrical stimulation therapy to be applied to the subject based on the category of AF; and driving one or more electrodes of the wearable device to apply the selected electrical stimulation therapy to the subject.

According to some applications of the present invention there is also provided an apparatus comprising: a wearable device configured to be worn by a subject, the device comprising: a photoplethysmogram (PPG) sensor; and one or more electrodes; and at least one computer processor associated with the wearable device, the computer processor configured to: receive data from the PPG sensor and in response thereto sense a heart rate of the subject; based on the sensed heart rate, detecting that the subject has experienced and/or is experiencing an episode related to the heart rate; in response, at least in part, to detecting the heart rate related episode, prompting the subject to record an Electrocardiogram (ECG); based at least in part on the ECG, determining that the subject is currently experiencing and/or is predicted to be experiencing an atrial fibrillation episode; and treating the current and/or predicted atrial fibrillation episodes by applying electrical stimulation via one or more electrodes.

In some applications, the wearable device includes a wristband, and at least one of the one or more electrodes is configured to be placed near a median nerve and/or ulnar nerve of the subject when the wristband is worn in a predetermined configuration.

In some applications, the wearable device further comprises an accelerometer, and the computer processor is configured to prompt the subject to record an ECG based at least in part on data acquired by the accelerometer.

In some applications, the wearable device further comprises an accelerometer, and the computer processor is configured to determine that the subject is currently experiencing and/or is predicted to experience a atrial fibrillation episode based at least in part on data collected by the accelerometer.

In some applications, the computer processor is configured to determine that the subject is predicted to be experiencing an atrial fibrillation episode by detecting an increase in the incidence of premature atrial contractions and/or atrial tachycardia in the subject.

In some applications, the computer processor is further configured to receive an input indicative of at least one additional parameter selected from the group consisting of: the activity state of the subject, the dietary state of the subject, the emotional state of the subject, and the time of day, and the computer processor is configured to determine that the subject is currently experiencing and/or is predicted to be experiencing an atrial fibrillation episode based on at least one additional parameter in combination with the ECG.

In some applications, the computer processor is further configured to receive an input indicative of at least one additional parameter selected from the group consisting of: the method includes classifying episodes of the subject as episodes of the given category based on at least one additional parameter, and classifying episodes of the subject as episodes of the given category based on at least one additional parameter.

In some applications, the computer processor is further configured to determine that the subject is in a parasympathetic state, and the computer processor is configured to treat the current and/or predicted onset of atrial fibrillation by driving one or more electrodes of the wearable device to apply an electrical stimulation therapy to the subject with a frequency between 40Hz and 50 Hz.

In some applications, the computer processor is further configured to determine that the subject is in a sympathological state, and the computer processor is configured to treat the current and/or predicted atrial fibrillation episodes by driving one or more electrodes of the wearable device to apply an electrical stimulation therapy to the subject with a frequency between 1Hz and 5 Hz.

In some applications, at least one of the electrodes is a dual function electrode configured to have a sensing mode in which the dual function electrode is configured to record the ECG of the subject and a stimulation mode in which the computer processor is configured to apply electrical stimulation therapy to the subject via the dual function electrode.

According to some applications of the present invention there is also provided a method comprising: detecting a PPG signal of the subject using a wearable device comprising one or more electrodes; and using at least one computer processor associated with the wearable device: receiving data from a PPG sensor, and in response thereto, sensing a heart rate of the subject; based on the sensed heart rate, detecting that the subject has experienced and/or is experiencing an episode related to the heart rate; in response, at least in part, to detecting the heart rate related episode, prompting the subject to record an Electrocardiogram (ECG); determining that the subject is currently experiencing and/or is predicted to be experiencing an atrial fibrillation episode based at least in part on the ECG; and treating the current and/or predicted atrial fibrillation episodes by applying electrical stimulation via one or more electrodes.

According to some applications of the present invention there is also provided an apparatus comprising: a wearable device configured to be worn by a subject, the wearable device comprising one or more electrodes, and the wearable device configured to detect a heart related parameter of the subject; and a computer processor associated with the wearable device, the computer processor configured to: receiving the detected heart related parameter; identifying an AF episode by analyzing the detected heart related parameter, and in response to identifying the AF episode, analyzing Heart Rate Variability (HRV) of the subject for a given period of time before the AF episode begins; based at least in part on analysis of the HRV of the subject within a given period of time prior to the onset of the AF episode, an electrical stimulation therapy to be applied to the subject is selected and one or more electrodes of a wearable device are driven to apply the selected electrical stimulation therapy to the subject.

In some applications, the computer processor is additionally configured to receive an input indicative of at least one additional parameter selected from the group consisting of: the method further includes selecting an electrical stimulation therapy to be applied to the subject based on the at least one additional parameter in combination with analysis of the HRV of the subject for a given period of time prior to the onset of the AF episode.

In some applications, the computer processor is configured to classify the AF as being interrelated with a parasympathetic state of the subject or a sympathetic state of the subject based at least in part on an analysis of the HRV of the subject within a given period of time prior to onset of the AF episode.

In some applications, the at least one computer processor is additionally configured to receive an input indicative of at least one additional parameter selected from the group consisting of: the method further includes classifying the AF as being interrelated with the parasympathetic state of the subject or the sympathetic state of the subject based on the at least one additional parameter in combination with analysis of the HRV of the subject for a given period of time prior to onset of the AF episode.

According to some applications of the present invention there is also provided a method comprising: detecting a heart related parameter of the subject using a wearable device comprising one or more electrodes; and using at least one computer processor associated with the wearable device: receiving the detected heart related parameter; identifying an AF episode by analyzing the detected heart related parameter; in response to identifying an AF episode, analyzing Heart Rate Variability (HRV) of the subject for a given period of time prior to the onset of the AF episode; selecting an electrical stimulation therapy to apply to the subject based at least in part on an analysis of the subject's HRV within a given period of time prior to the onset of the AF episode; and driving one or more electrodes of the wearable device to apply the selected electrical stimulation therapy to the subject.

According to some applications of the present invention there is also provided an apparatus comprising: a wearable device configured to be worn by a subject, the wearable device comprising one or more electrodes, and the wearable device configured to detect a heart related parameter of the subject; and a computer processor associated with the wearable device, the computer processor configured to: receiving the detected heart related parameter; identifying an AF episode by analyzing the detected heart related parameter, in response to identifying the AF episode, analyzing at least one physiological parameter of the subject for a given period of time before the AF episode begins, the physiological parameter selected from the group consisting of heart rate, HRV, and heart rate recovery, selecting an electrical stimulation therapy to be applied to the subject based at least in part on the analysis of the at least one physiological parameter for the given period of time before the AF episode begins, and driving one or more electrodes of the wearable device to apply the selected electrical stimulation therapy to the subject.

According to some applications of the present invention there is also provided an apparatus comprising: a wrist-wearable device configured to be placed on a subject's wrist in a predetermined configuration, the wrist-wearable device comprising one or more electrodes, and the electrodes being arranged such that when the wrist-wearable device is placed on the subject's wrist in a predetermined arrangement, the electrodes are arranged in proximity to a nerve selected from the group consisting of: ulnar and median nerves; and a computer processor configured to treat an atrial fibrillation related condition by delivering electrical stimulation current to the selected nerve via the electrodes at a frequency between 40Hz and 50 Hz.

In some applications, the one or more electrodes include at least two wrist-facing electrodes, the at least two wrist-facing electrodes being arranged such that when the wrist-wearable device is placed on the wrist of the subject in a predetermined arrangement, each of the two electrodes is disposed on a respective side of the selected nerve.

In some applications, each of the wrist-facing electrodes is shaped to have a long edge and a short edge, and the ratio between the length of the long edge and the length of the short edge is at least 3:2.

In some applications, the wrist-facing electrode is disposed such that a long edge of the wrist-facing electrode is substantially aligned with a length direction of the selected nerve when the wrist-wearable device is placed on the subject's wrist in a predetermined arrangement.

According to some applications of the present invention there is also provided a method comprising: identifying that the subject is experiencing an atrial fibrillation related condition; in response thereto, placing a wrist wearable device on the subject's wrist in a predefined configuration, the wrist wearable device comprising one or more electrodes, and the electrodes being arranged such that when the wrist wearable device is placed on the subject's wrist in the predefined configuration, the electrodes are arranged in proximity to a nerve selected from the group consisting of the ulnar nerve and the median nerve; and treating the atrial fibrillation-related condition by delivering electrical stimulation current to the selected nerve via the electrodes at a frequency between 40Hz and 50 Hz.

According to some applications of the present invention there is also provided an apparatus comprising: a wearable device configured to be worn by a subject, the wearable device comprising a plurality of electrodes; and a computer processor associated with the wearable device, the computer processor configured to: recording an Electrocardiogram (ECG) of the subject via a plurality of electrodes, reducing the incidence of AF in the subject by delivering an electrical stimulation current into a nerve of the subject; and adjusting delivery of the electrical stimulation current into the nerve of the subject after the ECG has been recorded within a given period of time prior to delivery of the electrical stimulation current.

According to some applications of the present invention there is also provided a method comprising: recording an Electrocardiogram (ECG) of the subject using a wearable device comprising one or more electrodes; and using at least one computer processor associated with the wearable device: receiving an Electrocardiogram (ECG) of the subject; reducing the incidence of AF in a subject by delivering an electrical stimulation current into a nerve of the subject; and adjusting delivery of the electrical stimulation current into the nerve of the subject after the ECG has been recorded within a given period of time prior to delivering the electrical stimulation current.

According to some applications of the present invention there is also provided an apparatus comprising: a module comprising a plurality of electrodes; and a computer processor associated with the module, the computer processor configured to: delivering an electrical stimulation therapy into a nerve of the subject via the electrodes, the electrical stimulation therapy configured to reduce the occurrence of AF and/or arrhythmia events, detecting a physiological parameter of the subject before and after delivering the electrical stimulation therapy, and in response thereto, determining an effect of the respective therapy; detecting an event associated with the respective therapy, the event selected from the group consisting of: the time of day of the respective treatment, and the dietary status of the subject during the respective treatment, correlating the effect of the respective treatment with the event associated with the respective treatment, and optimizing future treatment of the subject based on correlating the effect of the respective treatment with the event associated with the respective treatment.

According to some applications of the present invention there is also provided a method comprising: delivering an electrical stimulation therapy into a nerve of the subject, the electrical stimulation therapy configured to reduce the occurrence of AF and/or arrhythmia events; detecting a physiological parameter of the subject before and after delivery of the electrical stimulation therapy, and determining an effect of the respective therapy in response thereto; detecting an event associated with the respective therapy, the event selected from the group consisting of: time of day of the respective treatment, and the subject's dietary status during the respective treatment; correlating the effects of the respective treatments with events associated with the respective treatments; and optimizing future treatment of the subject based on correlating the effects of the respective treatments with events associated with the respective treatments.

According to some applications of the present invention there is also provided an apparatus comprising: one or more electrodes configured to be placed on the skin of a subject's wrist and in proximity to a nerve selected from the group consisting of ulnar nerve and median nerve; and a computer processor configured to: driving an electrical stimulation signal into the selected nerve via the electrode, the electrical stimulation signal configured to reduce the occurrence of AF and/or arrhythmia events; increasing the intensity of the electrical stimulation signal in response to receiving an input indicating that the electrical stimulation signal does not cause any sensation in the vicinity of the electrode; and in response to receiving an input indicating that the electrical stimulation signal causes involuntary movement of a portion of the subject's body in the vicinity of the electrode, decreasing the intensity of the electrical stimulation signal.

In some applications, the apparatus further comprises a user interface, and the computer processor is configured to receive, from the subject via the user interface, an input indicating that the electrical stimulation signal does not cause any sensation in the vicinity of the electrode and/or an input indicating that the electrical stimulation signal causes involuntary movement of a portion of the subject's body in the vicinity of the electrode.

According to some applications of the present invention there is also provided an apparatus comprising: one or more electrodes configured to be placed on the skin of a subject's wrist and in proximity to a nerve selected from the group consisting of ulnar nerve and median nerve; and a computer processor configured to: driving an electrical stimulation signal into the selected nerve via the electrode, the electrical stimulation signal configured to reduce the occurrence of AF and/or arrhythmia events; receiving input from the subject indicating a response of the subject's body in proximity to the electrode to the electrical stimulation signal; and setting the intensity of the electrical stimulation signal such that the electrical stimulation signal causes a sensation in the vicinity of the electrode, but does not cause involuntary movement of a portion of the subject's body in the vicinity of the electrode.

In some applications, the apparatus further comprises a user interface, and the computer processor is configured to receive input from the subject via the user interface.

According to some applications of the present invention there is also provided an apparatus comprising: one or more electrodes configured to be placed on the skin of a subject's wrist and in proximity to a nerve selected from the group consisting of ulnar nerve and median nerve; and a computer processor configured to: driving an electrical stimulation signal into the selected nerve via the electrodes at a given voltage; detecting a current of the electrical stimulation signal when the electrode is in good contact with the skin of the subject's wrist; and generating an output indicating that at least one of the electrodes should be moved in response to the current being below the threshold.

In some applications, in response to the current being below a threshold, the computer processor is configured to generate an output indicating that at least one of the electrodes should be moved closer to the selected nerve.

According to some applications of the present invention there is also provided an apparatus comprising: one or more electrodes configured to be placed on the skin of a subject's wrist and in proximity to a nerve selected from the group consisting of ulnar nerve and median nerve; and a computer processor configured to: driving an electrical stimulation signal into the selected nerve via the electrode at a given current; detecting a voltage of the electrical stimulation signal when the electrode is in good contact with the skin of the subject's wrist; and generating an output indicating that at least one of the electrodes should be moved in response to the voltage being above the threshold.

In some applications, in response to the voltage being above a threshold, the computer processor is configured to generate an output indicating that at least one of the electrodes should be moved closer to the selected nerve.

According to some applications of the present invention there is also provided an apparatus comprising: one or more electrodes configured to detect an ECG signal of a subject; and a computer processor configured to: receiving a detected ECG signal; analyzing a plurality of heartbeat sections of the detected ECG signal corresponding to a plurality of heartbeats; analyzing QRS complex segments of the detected ECG signal corresponding to individual heartbeats; and identifying and/or classifying an AF and/or arrhythmia event based at least in part on analyzing a combination of the plurality of heart beat segments of the detected ECG signal and the QRS complex segment of the detected ECG signal.

In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following detailed description.

Drawings

Exemplary embodiments are illustrated in the accompanying drawings. The dimensions of the components and features shown in the figures are generally chosen for convenience and clarity of presentation and are not necessarily shown to scale. These figures are listed below.

1A-1B are schematic diagrams of exemplary subject monitoring and treatment systems including a wearable device and one or more external computing devices, according to some applications of the invention;

2A-2C are illustrations of alternative views of an exemplary wearable device according to some applications of the invention;

2D-2E are schematic diagrams of modules configured to apply neuromodulation therapy to a subject and/or monitor the subject, in accordance with some applications of the present invention;

FIG. 3A is a schematic cross-sectional view of an exemplary module of the device of the present disclosure including two stimulation electrodes disposed about an inner skin surface of a wrist/forearm, showing the location of the median nerve and ulnar nerve relative to the inner skin surface of the wrist/forearm, and according to some applications of the invention;

FIG. 3B is a schematic illustration of a human wrist/forearm with the device of the present disclosure wrapped around and closed around the human wrist/forearm, according to some applications of the invention;

figures 3C-3D illustrate additional alternatives for arranging the stimulation electrodes of the present disclosure with respect to the median nerve, according to some applications of the present invention;

FIG. 4 is a schematic diagram of functional steps in a method of monitoring and treating a subject using, for example, the exemplary system described with reference to FIGS. 1A-1B, according to some applications of the present invention;

5A-5D are graphs showing experimental results of stimulation therapy performed on atrial fibrillation subjects according to some applications of the present invention; and

fig. 6 is a graph showing experimental results of stimulation therapy performed on atrial fibrillation subjects according to some applications of the present invention.

Detailed Description

Disclosed herein are systems and methods for delivering electrical energy in the form of electrical stimulation signals generated according to specified signal parameters to administer neuromodulation therapy to a subject to reduce and/or mitigate the occurrence of Atrial Fibrillation (AF), additional arrhythmia diseases, and/or additional cardiovascular diseases.

As used herein, "treatment" may refer to any change, modification, effect, modulation, and/or treatment action to one or more physiological conditions, states, properties, characteristics, functions, and/or activities.

As used herein, "electrical neuromodulation," "neuromodulation," and/or "neural stimulation" may be used interchangeably to refer to electrical, electromagnetic, or electromechanical neuromodulation of a neural structure or nerve, such as low-level electrical neural stimulation. In some embodiments, neuromodulation is performed in a non-invasive or non-invasive manner, i.e., electrical energy is delivered to the neural structure via percutaneous or transdermal delivery.

In some embodiments, the present disclosure provides for detecting current and/or upcoming AF or other arrhythmia-related conditions in a subject, such as Atrial Tachycardia (AT), atrial premature beat complex/atrial premature beat complex (APC or PAC) burden, or an acute increase in ventricular premature beat complex/ventricular premature beat complex (VPC or PVC). In some embodiments, the upcoming AF or other arrhythmia-related condition may be detected based at least in part on a particular precursor (specified precursor) detected (e.g., an increase in PAC in the subject, e.g., premature heartbeat originating from the atrium or two upper chambers of the heart).

As used herein, an "arrhythmia-related condition" or "arrhythmia-related event" may refer broadly to any one or more of AF, atrial premature beat complex (APC/PAC), acute atrial premature beat complex (VPC/PVC), supraventricular tachycardia (SVT), atrial Tachycardia (AT), atrial flutter, atrioventricular node reentry tachycardia (AVNRT), paroxysmal supraventricular tachycardia (PSVT), atrioventricular reentry tachycardia, pre-excitation syndrome, ventricular Tachycardia (VT), torsade pointes (TdP), long QT syndrome, cardiac conduction block, and/or sick sinus syndrome.

In some embodiments, detection of the onset of an arrhythmia-related event may be based at least in part on continuous, periodic, or intermittent monitoring and analysis of heart activity of the subject, e.g., monitoring of heart rate and cardiac cycle of the subject. As used herein, "heart activity", "heart function", "heart activity" may be used interchangeably to refer to various parameters for assessing, estimating and/or quantifying heart rate and heart rate variability. In some embodiments, heart activity may be monitored using any suitable heart activity sensor or sensors, such as an Electrocardiogram (ECG), which may be a portable ECG sensor, such as a Holter electrocardiograph monitor (Holter monitor), photoplethysmogram (PPG) sensor, or others.

In some embodiments, upon detection of a current and/or upcoming arrhythmia-related condition, the present disclosure then provides specific procedures for conducting neuromodulation therapy on a peripheral nerve of a subject (e.g., one or more of the median nerve, ulnar nerve, and/or radial nerve in the subject). In some embodiments, the present disclosure provides for administering a neuromodulation treatment process to the median nerve of a subject.

Taking into account background factors, neuromodulation of the median and/or ulnar nerves plays a critical role in the sympathetic and parasympathetic activities of the autonomic nervous system. Thus, stimulation of the median nerve and/or ulnar nerve may enhance parasympathetic activity of the vagus nerve and inhibit sympathetic activity of the cardiac nerve, and thus reduce heart rate, regulate heart rate, and correct and prevent arrhythmias. Neuromodulation of the median and ulnar nerves may also elicit neurohormonal responses: endorphins are secreted to reduce stress-related hormones, thereby alleviating stress and improving sleep.

With respect to electrical nerve stimulation, the term "stimulation signal" refers to a voltage/current signal applied between a pair of electrodes (attached to a target body part, such as an electrical nerve stimulating at least one nerve in the target body part).

In some embodiments, the stimulation signals of the present disclosure are applied to the median nerve and/or ulnar nerve in the forearm of the subject. In some embodiments, the stimulation signals may be applied via one or more pairs of electrodes configured to attach to a designated body part of the subject and deliver the signals to the median nerve and/or ulnar nerve.

In some embodiments, stimulation of peripheral nerves (e.g., median nerve) is performed in a non-invasive manner by transdermal or transdermal delivery of electrical energy in the form of an electrical stimulation signal generated in accordance with specified signal parameters.

In some embodiments, details of the treatment process and specified signal parameters may be determined based on analyzing one or more heart activity related parameters in the subject, such as Heart Rate Variability (HRV), heart rate recovery, heart rate reserves, atrial extra-systole, ventricular extra-systole, and HRV related parameters such as RR intervals, average interval between normal heartbeats (AVNN), standard deviation of NN intervals (SDNN), root mean square (rMSSD) of continuous differences between normal heartbeats, pNN50, low frequency activity (LF), and high frequency activity (HF).

In some embodiments, the details of the course of treatment and the specified signal parameters may be further determined based on subject state-related parameters, such as the activity state of the subject, the dietary state of the subject, and the emotional state of the subject, wherein at least some of these data may originate from subject monitoring or may be self-reported by the subject.

In some embodiments, the present disclosure may further use the cardiac activity related parameters and/or data and/or subject related parameters to detect an activation state of a particular component of the subject's autonomic nervous system, such as the Sympathetic Nervous System (SNS) and/or Parasympathetic Nervous System (PNS). In some embodiments, the present disclosure may be further configured to correlate the arrhythmia-related condition with a sympathetic or parasympathetic state of the subject, wherein details of the treatment process and specified signal parameters may be further determined based on the correlation.

In some embodiments, details of the treatment process may include, but are not limited to, the timing of the treatment session (s)/session(s), the number and total duration of the treatment session(s), and/or the number and duration of cycles to turn on/off the treatment session(s). In some embodiments, the specified signal parameters may be determined based at least in part on

In some embodiments, the specified parameter or "stimulation signal parameter" of the stimulation signal may broadly include any parameter that characterizes the electrical stimulation signal applied between the electrode pairs, including, but not limited to, a total signal duration, a signal waveform (e.g., sinusoidal, triangular, rectangular, and/or sawtooth waveform), a signal amplitude (e.g., maximum, minimum, medium, and/or average amplitude), a signal intensity (e.g., maximum, minimum, medium, and/or average intensity), a signal frequency, a signal pulse parameter (e.g., pulse duration and/or inter-pulse time interval) when the stimulation signal comprises a series of pulses, and/or a parameter that characterizes the synchronization of the stimulation signal with one or more other signals and/or reference activities (e.g., heart activity of the subject).

Thus, in some embodiments, upon detecting a current or upcoming arrhythmia-related condition in a subject, the present disclosure may be configured to determine details of a treatment procedure and/or specified signal parameters based at least in part on the detected cardiac activity-related parameters and/or subject state-related parameters. In some embodiments, the present disclosure is then configured to apply the therapeutic procedure to the subject by delivering a stimulation signal according to the determined therapeutic procedure, wherein the stimulation signal is delivered non-invasively to at least the median nerve of the subject, and wherein the analog signal has a frequency between 40-50Hz (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 Hz).

In some embodiments, when the arrhythmia-related condition correlates with parasympathetic status of the subject, the stimulation signal is configured to be delivered at a frequency between 40-50Hz (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 Hz). As demonstrated by the data provided herein, it has been found that such stimulation signal frequency in combination with additional stimulation signal parameters generally reduces the occurrence of arrhythmia-related conditions in a subject in a parasympathetic state, thereby indicating an improvement in cardiovascular distress and/or a reduction in cardiovascular exacerbations.

In some embodiments, when the arrhythmia-related condition correlates with the sympathetic nerve state of the subject, the stimulation signal is typically delivered at a frequency between 1-5Hz (e.g., 1, 2, 3, 4, or 5 Hz). As demonstrated by the data provided herein, such stimulation signal frequencies in combination with additional stimulation signal parameters have been found to reduce the occurrence of arrhythmia-related conditions in a subject in a sympathological state, thereby indicating an improvement in cardiovascular distress and/or a reduction in cardiovascular exacerbations.

Taking into account background factors, the Sympathetic Nervous System (SNS) is usually activated in response to mental or physical stress and may be associated with elevated blood pressure, increased blood flow to muscles and lungs, decreased blood flow to the digestive and reproductive systems, and release of stress hormones and glucose to provide rapid energy. In contrast, the Parasympathetic Nervous System (PNS) is usually activated in a recovery state, such as during rest or sleep, after meals, and is associated with a slowing of heart rate and respiration, a decrease in blood pressure, an increase in intestinal activity and an increase in blood flow to the digestive tract, a decrease in stress hormones, and a release of neurotransmitters such as acetylcholine which regulate muscle contraction.

Thus, in some embodiments, activation of a detected SNS in a subject may result in a determination that an arrhythmia-related condition correlates with a "sympathetic state" of the subject. PNS activation detected in a subject may result in a determination that an arrhythmia-related condition correlates with the subject's "parasympathetic state".

Fig. 1A-1B are schematic diagrams of exemplary subject monitoring and treatment systems including a wearable device 10 and one or more external computing devices 28, according to some applications of the invention. Reference may also be made to fig. 2A-2C, which are illustrations of alternative views of an exemplary wearable device 10 according to some applications of the invention.

In some embodiments, the wearable device 10 is configured to be worn on the wrist of a subject, e.g., the wearable device is configured as a wristband (as shown), a bracelet, a strap, a cuff, a ring, a waistband, a collar, or a chain. The device or a portion thereof (e.g., module 15, described in detail below) may be embedded within an article of clothing (e.g., a sleeve of a shirt), or embedded within a glove or sock, or otherwise removably attached to the subject's body at a desired body part. In some embodiments, the device or a portion thereof (e.g., module 15) may be held separately using a removable patch, decal, or adhesive bandage (adhesive bandage). As used herein, an object may be said to be "held independently" against a body part when the object is held in place after the object is placed on or attached to the body part without any action on the part of the user. Alternatively or additionally, the wearable device is configured to be worn on a different portion of the subject's body.

In some embodiments, the device 10 is configured to perform subject monitoring and subject treatment (i.e., stimulation) functions by switching/alternating between a monitoring mode and a treatment mode. For example, after a (preset) stimulation period, the device may automatically switch back to the monitoring mode to obtain updated values of the monitoring data and the effect of the stimulation. The stimulation parameters are adjusted accordingly (i.e., taking into account updated values). The device may then switch back to the stimulation mode and resume applying stimulation, and so on.

In general, the wearable device includes one or more electrodes 12a, 12b configured to provide neuromodulation therapy to the subject. In some embodiments, at least one of the electrodes may be configured to also perform one or more sensing functions. For example, the at least one electrode may be configured to record an Electrocardiogram (ECG) of the subject. In some embodiments, at least one electrode is a dual function electrode configured to perform a neuromodulation function in a first mode and to perform a sensing or monitoring function in a second mode. Typically, the wearable device includes one or more additional sensors, such as an optical sensor (e.g., a photoplethysmogram (PPG) sensor 11), an accelerometer 13, and/or an ECG sensor 16.

In general, the wearable device includes a user interface 14, which user interface 14 may include a display screen, optionally a touch screen. The user interface 14 is used to provide output to a user and/or to receive input from a user. In some embodiments, the wearable device includes a control module 18 (including, for example, one or more hardware processors). In some embodiments, at least the electrodes 12a, 12b and one or more of the PPG sensor 11, accelerometer 13, ECG sensor 16, and control module 18 are housed in a detachable module 15 of the device 10, as will be described further below.

The control module 18 may include one or more hardware processors, random Access Memory (RAM), and one or more non-transitory computer-readable storage devices, such as storage device 18a. The components of control module 18 may be co-located or distributed, or control module 18 may be configured to run as one or more cloud computing "instances," "containers," "virtual machines," or other types of packaged software applications known in the art.

The storage device 18a may have program instructions and/or components stored thereon that are configured to operate the control module 18. The program instructions may include one or more software modules, which may include an operating system with various software components and/or drivers for controlling and managing general system tasks (e.g., memory management, storage device control, power management, etc.) and facilitating communication between the various hardware and software components. The control module 18 may operate by loading instructions of the various software modules into its RAM when executed by the hardware processor(s) comprising the control module 18.

The control module 18 as described herein is only an exemplary embodiment of the present invention and may be implemented in practice in hardware only, in software only, or in a combination of both hardware and software. The control module 18 may have more or fewer components and modules than shown, may combine two or more components, or may have different component configurations or arrangements. The control module 18 may include any additional components that enable it to function as an operable computer system, such as a motherboard, a data bus, a power supply, a network interface card, a display, an input device (e.g., user interface 14), and the like. Moreover, the components of control module 18 may be co-located or distributed, or the system may be configured to run as one or more cloud computing "instances," "containers," "virtual machines," or other types of packaged software applications known in the art.

In general, the wearable device or any of its modules (e.g., module 15) is configured to communicate with one or more external computing devices 28 (as shown in fig. 1A-1B), which may include a computer processor of a local computing device, such as a smartphone 30, tablet device 32, and/or personal computer 34, and/or a remote computing device or remote server, such as a cloud-based remote server 36. For example, the external computing device may receive data from the control module 18 of the wearable device, and may then process the data, for example, using the techniques described herein. Alternatively or additionally, the external computing device may send data and/or instructions to the control module 18 of the wearable device. The specification and claims include references to certain functions that are performed by a computing device. Typically, such functions are performed by the control module 18, the external computing device 28, and/or a combination thereof.

In some embodiments, the device 10 may include a stimulation signal generator 17 that includes a power source (not shown). The stimulation signal generator 17 is configured to generate an electrical signal (e.g., a voltage signal or a current signal) between the stimulation electrodes 12a, 12b based on the signal parameters determined by the device 10. The stimulation parameters may specify a time dependence of the generated electrical signal. In particular, in some embodiments, the stimulation signal generator 17 is configured to automatically adjust the voltage and frequency applied between the stimulation electrodes 12a, 12b, such as to achieve desired signal parameters. The stimulation signal generator 17 may comprise, for example, an AC current source or an electrical signal generator such that the intensity, frequency, and waveform of the voltage/current generated by the stimulation signal generator 17, including parameters characterizing the voltage/current (including continuous voltage/current pulses, intermittent voltage/current pulses, and burst modes), may be controllably varied in accordance with the stimulation parameters, thereby affecting neuromodulation of at least one nerve in the target body part as described herein.

The communication unit 19 is configured to send and/or receive information to/from external agents, such as smartphones, smartwatches, smartbands, tablets, personal computers and/or remote servers. The transmission and reception of information (e.g. monitored cardiac parameters, determined stimulation parameters) may be achieved wirelessly and/or wiredly. The communication unit 19 may be configured to communicate over a cellular network and/or Wi-Fi (e.g., with a user's cloud storage, a user's personal computer, a user's healthcare provider's computer system, and/or a user's doctor/caregiver's personal computer). Alternatively, or in addition, the communication unit 19 may be configured to communicate over short distances, for example by bluetooth, NFC (near field communication) technology and/or Wi-Fi (e.g. with a smartphone or tablet of the user). In particular, in some embodiments, the communication unit 19 may be used to relay information from the device 10 to the user's smart phone/smart watch and to relay commands from the user's smart phone/smart watch to the device 10, thereby facilitating control and operation by the smart phone/smart watch.

In some embodiments, the device 10 is configured to send information to and receive information from the control module 18 and/or an external agent (or external device), such as a user's smart phone, smart watch, home hub, through wireless communication or wired communication (e.g., through a USB cable). The measurement data may be sent to the control module 18 and/or the external computing device 28, such as a smartphone 30, tablet 32, computer 34, or remote cloud server 36, or the like, where the measurement data is processed. In some embodiments, the determination of the stimulation parameters may also be performed by the control module 18 and/or the external agent using the values of the obtained monitoring data. The values of the obtained monitoring data and the stimulation parameters may be stored in a memory on the external agent for future reference. The stimulation parameters may also be transmitted directly from the external agent to the device 10, independent of the acquired data, e.g. preset parameters of a certain stimulation protocol/protocol, to achieve the desired physiological effect.

In some embodiments, the wearable device and/or the external computing device are configured to receive data from one or more external sensors 23 (as shown in fig. 2B) and/or one or more additional sensors built into the wearable device, such as acoustic sensors, optical sensors, pressure sensors (e.g., configured to measure blood pressure), and/or visual sensors.

Generally, the wearable device 10 is configured to be placed on a subject's wrist in a predetermined configuration. Referring to fig. 2C, which is a schematic illustration of a view of the wrist-facing side of the wearable device (i.e., the side of the wearable device configured to face the wrist of the subject), note that electrodes 12a, 12b are wrist-facing electrodes configured to contact the skin of the wrist of the subject. The wrist-facing electrode is typically arranged such that when the wrist-wearable device is placed on the wrist of a subject in a predefined arrangement, the wrist-facing electrode is disposed near the median nerve or another upper peripheral nerve of the subject. For example, in the device configuration shown in fig. 1A-1B, the device is configured such that when the device is placed on the subject's wrist and the screen is up, the wrist-facing electrodes 12a, 12B are disposed near the subject's median nerve or another upper limb peripheral nerve.

In some embodiments, the wearable device 10 is configured to be placed against, held by, or placed on a target body part of a subject such that both stimulation electrodes 12a, 12b are in skin or transdermal contact with the target body part. As used herein, "skin contact" or "transdermal contact" between a conductive object and a body part may refer to direct contact between skin on the body part and the conductive object, as well as indirect contact between skin on the body part and the conductive object (e.g., via a gel layer, saline solution, or the like, or a medium carrying or impregnated with such liquid between the object and the body part), which allows the conductive object to be electrically associated with the body part.

Notably, although some sensing and/or neuromodulation techniques and algorithms used thereof are described herein with reference to the wearable device 10, the scope of the present invention includes practicing any of the sensing and/or neuromodulation techniques and algorithms used thereof without using the wearable device 10. For example, such techniques and algorithms may be practiced without a wearable device using electrodes and/or sensors placed in contact with the subject's body, and/or using a wearable device worn on a portion of the subject's body other than the subject's wrist. In some embodiments, one or more of the median nerve, ulnar nerve, tibial nerve, fibular nerve, subcostal nerve, intraspinal nerve (intravertebral nerves), and/or different nerves of the subject are stimulated.

In general, the wearable device 10 includes a pair of wrist-facing electrodes 12a, 12b. In some embodiments, the device 10 is configured to provide neuromodulation therapy by delivering an electrical signal from a first one of the wrist-facing electrodes 12a, 12b to the other one of the wrist-facing electrodes 12a, 12b, such that the electrical signal is delivered to the median nerve and/or another peripheral nerve of the subject, such as the median nerve, via skin contact. As described below, in some embodiments, the signal is biphasic, in which case the direction of the drive signal alternates between the electrodes. Referring again to fig. 2C, in some embodiments, the wrist-facing electrodes 12a, 12b are shaped such that the electrodes have a rectangular, elliptical, semicircular, or racetrack-shaped profile defining the major and minor axes of the electrodes. The ratio of the length of the longitudinal axis to the length of the transverse axis is typically at least 3:2 (e.g., at least 2:1). Generally, the wrist-facing electrodes 12a, 12b are oriented such that when the wrist-wearable device is placed on the wrist of a subject in a predefined arrangement, the longitudinal axis of each electrode 12a and 12b is disposed substantially parallel to the longitudinal axis of the median nerve or peripheral nerve of the other upper limb of the subject. In this way, the wearable device is configured to drive an electrical signal from a first electrode facing the wrist to a second electrode facing the wrist via the median nerve or another upper limb peripheral nerve, but not substantially leak the signal to other tissues and/or nerves in the vicinity of the electrodes.

In general, the wearable device 10 is configured to provide neuromodulation therapy for subjects experiencing arrhythmia-related conditions (such as AF, acute PAC, PVC, occurrence of supraventricular tachycardia, and/or atrial tachycardia). Typically, treatment is provided by the device 10 which transmits electrical signals from a first one of the wrist-facing electrodes 12a, 12b to the other one of the wrist-facing electrodes, such that the electrical signals pass through the median nerve or the other upper peripheral nerve of the subject, as described above. As described below, in some embodiments, the signal is biphasic, in which case the direction of the drive signal alternates between the electrodes. The signal typically has any one of a sinusoidal waveform, a triangular waveform, a rectangular waveform and/or a sawtooth waveform. Typically, during a given treatment session, the signal is applied at a switching duty cycle, wherein the signal is applied for 5 to 30 seconds and then turned off for a period of 0 to 5 seconds.

The signal is typically driven at a frequency between 40-50Hz (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50Hz or any frequency therebetween). As demonstrated by the data provided herein (as described below with reference to fig. 5A-5D), such stimulation parameters have been found to generally reduce the occurrence of AF and/or arrhythmia disease (indicating an improvement in cardiovascular pain and/or a reduction in cardiovascular exacerbations). The inventors have also found that stimulating certain subjects at a frequency between 1-5Hz (e.g., 1, 2, 3, 4, or 5Hz or any fractional frequency therebetween) can reduce the occurrence of AF and/or arrhythmia disease (indicating an improvement in cardiovascular pain and/or a reduction in cardiovascular exacerbations). Thus, in some embodiments, the signal is driven at a frequency between 1-5Hz (e.g., 1, 2, 3, 4, or 5 Hz). In some embodiments, the system selects which signal parameters to apply to the subject during a given treatment based on one or more detected parameters and/or additional inputs, as described in further detail below.

As described in further detail herein, in many subjects, 40-50Hz stimulation was found to reduce the occurrence of AF and/or arrhythmia disease. Also as previously described, in some subjects, 1-5Hz stimulation was found to reduce the incidence of AF and/or arrhythmic diseases. Stimulation at 40-50Hz has been shown to reduce the occurrence of AF and/or arrhythmia disorders that correlate with parasympathetic status or vagal tone (which may be the case in subjects with idiopathic AF and/or arrhythmia disorders), and stimulation at such frequencies restores the autonomic balance in such subjects. It has further been shown that 1-5Hz stimulation reduces the occurrence of AF and/or arrhythmia disease that correlates with excessive sympathetic tone (which may be the case in subjects with non-primary AF and/or arrhythmia disease, such as scarred subjects on the heart, and/or CHF subjects or permanently AF patients) and that this frequency of stimulation restores the autonomic balance in these subjects.

In view of the above, in some embodiments, in response to detecting a current imbalance of the subject's autonomic nervous system, a stimulus is delivered to restore the subject's autonomic nervous balance, regardless of whether the subject is experiencing an AF and/or arrhythmia episode, in order to reduce the risk of the subject experiencing other clinical episodes. For example, if the subject's parasympathetic tone is too high and/or its sympathetic tone is too low, this may result in bradycardia and/or hypotension. In some embodiments, the system detects that the subject's parasympathetic tone is too high and/or its sympathetic tone is too low, e.g., by detecting that its HRV is high and/or based on the subject's heart rate or heart rate recovery. In response to detecting this condition, the subject is stimulated with a signal having a frequency of 40-50Hz (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50Hz or any fractional frequency therebetween) to restore autonomic balance by decreasing parasympathetic tone and/or increasing sympathetic tone. Conversely, if the subject's sympathetic tone is too high and/or parasympathetic tone is too low, this may result in tachycardia, hypertension, worsening heart failure, sleep apnea and/or impaired recovery following myocardial infarction. In some embodiments, the system detects that the subject's sympathetic tone is too high and/or its parasympathetic tone is too low, e.g., by detecting that its HRV is low and/or based on the subject's heart rate or heart rate recovery. In response to detecting this condition, the subject is stimulated with a signal having a frequency between 1-5Hz (e.g., 1, 2, 3, 4, or 5Hz or any fractional frequency therebetween) to restore autonomic balance by decreasing sympathetic tone and/or increasing parasympathetic tone.

As described above, in some embodiments, at least one of the electrodes 12a, 12b is configured to perform a sensing function. For example, at least one of the electrodes may be configured to record an ECG of the subject. Referring to fig. 2B, in some embodiments, the wearable device includes one or more outwardly facing electrodes (i.e., the electrodes are configured to face away from the subject's wrist when the device is worn on the subject's wrist). In some embodiments, the wearable device is configured to record the ECG of the subject by deploying the ECG sensor 16 using the outwardly facing electrode as a first ECG electrode and one of the wrist-facing electrodes 12a, 12b as a second ECG electrode. The wearable device is thus configured to detect ECG signals between the subject's finger or thumb and the subject's wrist by the user placing the finger or thumb on the outwardly facing electrode 21.

In some embodiments, the wearable device 10 is configured to apply neuromodulation therapy and/or configure neuromodulation therapy parameters based on sensed and/or additional inputs, as described further below. Alternatively or additionally, the wearable device is configured to enable a user to apply therapy at regular intervals using the device, rather than in response to sensing an episode or potential episode. For example, purely by way of illustration, a user may use the device at a rate between once per day and once per month for a treatment session of between 5 minutes and 1 hour. In some embodiments, the control module 18 and/or the external computing device 28 are configured such that they adjust the application of the therapy when the user records an ECG within a given period of time (e.g., within 1 hour, 30 minutes, 10 minutes, or 5 minutes) of the applied therapy. In some embodiments, the condition of the current therapy is that the ECG has been recorded within a given period of time prior to the current therapy. In some embodiments, the condition of the current therapy is that the ECG has been recorded for a given period of time after the previous therapy. Typically, by conditioning the application of therapy to such an ECG recording, the system facilitates monitoring the efficacy of the therapy by allowing monitoring of the effect of the therapy on the subject's ECG (such monitoring being performed by a healthcare professional and/or automatically performed by the system).

Reference is now made to fig. 2D-2E, which are schematic illustrations of a module 15 configured to apply neuromodulation therapy to a subject and/or monitor the subject, in accordance with some applications of the present invention. In general, the module 15 is generally similar to the module 15 described above with reference to the wearable device 10. In some embodiments, the electrodes 12a, 12b, PPG sensor 11, accelerometer 13, ECG sensor 16, and/or control module 18 are housed in module 15, which typically have substantially similar functions as those described above. In some embodiments, the electrodes 12a, 12b are disposed around the wrist-facing side 15a of the module 15, and the PPG sensor 11, accelerometer 13, ECG sensor 16 may be disposed on opposite sides of the module 15, e.g., the outward-facing side 15b of the module 15. In other embodiments, one or more of PPG sensor 11, accelerometer 13, ECG sensor 16 may also be disposed around wrist-facing side 15a of module 15.

As noted above, although some sensing and/or neuromodulation techniques and algorithms used thereof are described herein with reference to wearable device 10, the scope of the present invention includes practicing any of the sensing and/or neuromodulation techniques and algorithms using one, both, and/or any suitable combination of wearable device 10 and module 15. For example, such techniques and algorithms may be practiced without a wearable device using electrodes and/or sensors placed in contact with the subject's body, and/or using a wearable device worn on a portion of the subject's body other than the subject's wrist. In some embodiments, one or more of the median nerve, ulnar nerve, radial nerve, tibial nerve, fibular nerve, subcostal nerve, intraspinal nerve, and/or different nerves of the subject are stimulated. In some embodiments, the module 15 is placed on a different portion of the subject's body, for example, the subject's chest (typically, the electrodes 12a, 12b contact the subject's skin, and the electrode 21 faces away from the subject's skin).

Reference is made to fig. 3A-3B. Fig. 3A is a schematic cross-sectional view of a human wrist/forearm 37 showing the location of the median and ulnar nerves relative to the inner skin surface of the wrist/forearm 37. Fig. 3A also shows an exemplary module 15 of the device 10 of the present disclosure, including two stimulation electrodes 12a, 12b disposed about a wrist-facing side 15a of the module 15, and an ECG electrode 16 disposed about an outward-facing side 15b of the module 15.

Fig. 3B is a schematic view of a human wrist/forearm 37 wrapped around and closing the device 10 of the disclosure. The device 10 comprises a module 15, the module 15 being positioned such that it faces the inner face of the wrist/forearm 37. The module 15 comprises two stimulation electrodes 12a, 12b (each exposed only on the inner surface of the wrist/forearm 37 and thus schematically shown by the dashed elongated shape).

As shown in fig. 3A-3B, the module 15 is disposed about the wrist/forearm 37 such that the stimulation electrodes 12a, 12B are positioned across either side of, for example, the median nerve 42 for simultaneous transdermal contact and delivery of stimulation signals to the median nerve 42. Fig. 3C-3D illustrate other alternatives of arranging the electrodes 12a, 12b relative to the median nerve 42, e.g., such that each of the electrodes 12a and 12b is positioned transversely (fig. 3C) or longitudinally (fig. 3D) across the median nerve 42.

By way of background, targeting median nerve represents an advantageous path for delivering an electrical stimulation signal intended to reduce arrhythmia-related events for the following reasons:

the median nerve has a cross-sectional area at the wrist that is significantly greater than that of other upper limb nerves, such as the ulnar nerve and the radial nerve, and

the centre is relatively close to the skin, which increases the electrical conduction of the electrical stimulation signal to the nerve.

Thus, in some embodiments, the present disclosure provides a design of the module 15 configured to ensure optimal positioning of the module 15 and the stimulation electrodes 12a, 12b relative to the median nerve 42 in order to maximize delivery of the stimulation signal to the median nerve 42.

In some embodiments, based on the positioning of the module 15 and the stimulation electrodes 12a, 12b relative to the median nerve 42, the same property of the median nerve 42, in conjunction with the ECG sensor 16, represents an advantageous path for measuring ECG signals with respect to the subject. Thus, in some embodiments, the module 15 is configured to record the subject's ECG using the ECG sensor 16 and one of the electrodes 12a, 12b by the subject placing a finger or thumb on the outwardly facing ECG sensor 16 and thereby recording an ECG signal between the subject's finger or thumb and the subject's wrist.

In some embodiments, module 15 may define a rigid, substantially planar body sized to extend substantially across the span of wrist/distal forearm 37, as represented by arrows A-A in fig. 3A-3B. In some embodiments, stimulation electrodes 12a, 12b may be disposed around wrist-facing side 15a of module 15 along a longitudinal dimension of module 15 so as to be positioned at a designated location relative to median nerve 42 crossing the approach of median nerve 42. In some embodiments, the electrodes 12a, 12B may be oriented about the module 15 such that the longitudinal axis X (as shown in fig. 3B) of each electrode is disposed on either side of the median nerve 42, proximate to and substantially parallel to the longitudinal axis of the median nerve 42 of the subject.

Thus, in some embodiments, the median nerve 42 may be electrically stimulated by closing an electrical conduction path between the stimulation electrodes 12a, 12b and a region of skin adjacent to or including a segment of the median nerve 42.

In some embodiments, the electrodes 12a, 12b may each have a width dimension measured between 1-15mm (e.g., 7 mm) and a length dimension measured between 2-35mm (e.g., 15 mm). In some embodiments, the distance Y between the electrodes 12a, 12B (as shown in FIG. 3B) may be in the range between 1-10mm, for example 4mm.

In some embodiments, the module 15 may be configured to be produced in a range of sizes and dimensions, each size and dimension being adapted to fit the anatomy and dimensions of the wrist/forearm of various users to ensure optimal placement of the module 15 and stimulation electrodes 12a, 12b and to maximize signal delivery to the median nerve. In some embodiments, the electrodes 12a, 12b may be square, oval, or any other common or non-conventional shape having a size and surface area within a range similar to the ranges described above.

With continued reference to fig. 3A-3B, in some embodiments, the present disclosure further provides a technique for ensuring optimal positioning of module 15 (and thus stimulation electrodes 12a, 12B) around the inner surface of the wrist to ensure maximum signal delivery to the median nerve. In some embodiments, the present technique is based on (i) measuring the current relative to the electrically conductive path between the stimulation electrodes 12a, 12b when the device 10 is used by a user and wrapped around the wrist of the user, and (ii) comparing the measured current to a predetermined baseline current that is indicative of the optimal positioning of the electrodes 12a, 12b relative to the subject. In some embodiments, when the measured current is below the baseline value, the device 10 of the present disclosure may issue an indication to the user and/or medical practitioner to adjust the positioning of the device until the measured current approaches or equals the baseline value.

The inventors have found that due to the unique nature of the median nerve (i.e., large cross-section and relative proximity to the skin surface), the maximum current value can be measured relative to the electrical conduction path between the stimulation electrodes 12a, 12b and the area of the skin proximate to or including a segment of the median nerve 42. Thus, the optimal positioning of the electrodes 12a and 12b relative to the median nerve 42 will represent a higher measured current value than all other possible positioning of the electrodes 12a, 12b about the inner surface of the wrist relative to a particular user. Table 1 below shows the results of experiments performed by the present inventors on three subjects. As can be seen from the results, for each subject, when the electrodes 12a, 12b are in the optimal placement (M represents "median"), the maximum current measurement is obtained at the suboptimal location (R represents "radius" and/or U represents "ulna" or U-distal represents "ulnar distal"). The values are in milliamperes (ma). The average current measurement represents at least 33 different measurements.

Table 1:

thus, with continued reference to fig. 3A-3B, and with returning reference to fig. 1B, in some embodiments, the present disclosure provides for measuring a maximum baseline current value for the subject that is indicative of an optimal positioning of the electrodes 12a, 12B relative to the path of the median nerve around the medial skin area of the wrist. In some embodiments, when a subject uses the device 10 of the present disclosure, the placement module 22 (shown in fig. 1B) may be configured to measure a current related to the electrical conduction path between the stimulation electrodes 12a, 12B and compare the measured current to a predetermined baseline current. In some embodiments, when the measured current is below the baseline value, placement module 22 may be configured to issue appropriate notifications to the user and/or healthcare practitioner to adjust the positioning of device 10. In some embodiments, placement module 22 may be configured to monitor device placement by performing current measurements on a planned, or periodic basis according to user requests.

Reference is now made to fig. 4, which is a schematic illustration of functional steps in a method of monitoring and treating a subject using, for example, the exemplary system described with reference to fig. 1A-1B and/or the exemplary apparatus described with reference to fig. 2A-2D and 3A-3B, according to some applications of the present invention. As described above, in some embodiments, the wearable device 10 includes one or more sensors, such as PPG sensor 11 and/or accelerometer 13, in addition to the electrodes 12a, 12b (which are configured to record the subject's ECG).

In some embodiments, the control module 18 and/or the external computing device 28 are configured to drive the wearable device to perform continuous, intermittent, and/or periodic monitoring, measurement, and data acquisition for the subject (step 58). For example, control module 18 and/or external computing device 28 are configured to collect data from internal sensors within device 10 (step 50), such as PPG measurements from PPG sensor 11, data from accelerometer 13, and/or an ECG signal from ECG sensor 16. In some embodiments, step 58 may include all-weather monitoring and treatment. Monitoring may be continuous or planned, for example, every predetermined number of minutes or hours, as suggested by the healthcare provider. In some embodiments, the monitoring may be based on the activity state of the subject as determined by the PPG/ECG sensor and the accelerometer, e.g., the monitoring may be initiated when the subject is stationary (as indicated by accelerometer data).

In some embodiments, control module 18 and/or external computing device 28 are configured to analyze the acquired data (step 60), such as PPG measurements, ECG signals, and/or data received from the accelerometer, and determine that (i) the subject may be experiencing an arrhythmia-related event, such as AF, PAC, AT, or (ii) predict that the subject is experiencing an arrhythmia-related event (e.g., in response to detecting HRV, heart rate recovery, and/or a change in heart rate). In general, the control module 18 and/or the external computing device 28 are configured to analyze data acquired from internal sensors (e.g., PPG sensor 11 and/or ECG sensor 16) (step 60) to detect, for example, heart rate related episodes, such as unexplained changes in heart rate, unstable heart rate, measurement of HRV, and/or changes in heart rate recovery, and in response thereto generate predictions, followed by stimulation therapy for prophylactic purposes.

In some embodiments, control module 18 and/or external computing device 28 are further configured to collect additional and/or other data, including, but not limited to:

data from one or more external sensors 23 (step 52), such as acoustic sensors, optical sensors, pressure sensors (e.g. configured to measure blood pressure) and/or visual sensors;

-obtaining an ECG signal for the subject using, for example, the ECG sensor 16 and/or an external ECG sensor (step 54);

-one or more subject-related activity states, emotional states, and/or physiological data, comprising (step 56):

o the subject's current and/or recent activity status (e.g., eating, lying down, sleeping, walking, running, exercising, driving, etc.),

o the subject's dietary status (e.g., hunger, current feeding, last feeding, etc.),

o the emotional state of the subject (e.g., tension, relaxation, active emotion, depression, anxiety, trauma, etc.), and/or

O other physical symptoms (e.g., fatigue, chest distress, palpitations, dizziness, fainting, headache, shortness of breath, chest "empty" sensation, acceleration or tremors of the heartbeat, jumping of the heart, throat pressure, coldness or coldness, dehydration), and/or

Other physiological parameters (e.g. blood related parameters, anemia, digestion related symptoms, insomnia, hormonal data).

In some embodiments, in steps 50 and 54, the following data sets may be obtained from PPG sensor 11 and/or ECG sensor 16 and/or other heart rate measurements:

HRV: heart rate variability,

-RR interval: the time that passes between two consecutive R-waves,

AVNN: the average interval between normal heart beats,

-SDNN: the standard deviation of the NN interval is used,

rMSSD: the root mean square of the continuous differences between normal heartbeats,

pNN50: average number of times per hour of continuous normal sinus (NN) interval change exceeding 50ms, and

-LF and HF: low frequency and high frequency activity.

In some embodiments, the subject-related parameters may be self-reported by the subject, for example, via the user interface 14. For example, the subject may be prompted to enter information regarding their activity status, dietary status, emotional status, and/or physical symptoms. In some embodiments, the subject is prompted, e.g., via user interface 14, to enter information regarding their lifestyle and/or activity. For example, the subject may be prompted to enter information regarding their emotional state, physical symptoms, and/or dietary status, as described above.

In some embodiments, control module 18 and/or external computing device 28 are configured or prompt the subject to input one or more of these data, and/or record an ECG for acquisition, such as sensor 16. Alternatively or additionally, the computing device prompts the subject to take additional measurements. Further alternatively or additionally, the control module 18 drives one or more sensors to automatically detect additional physiological parameters of the subject. In some embodiments, the control module 18 is configured to receive additional data from other sensors, such as acoustic sensors, pressure sensors, optical sensors, and/or visual sensors, which may be disposed within the wearable device or external to the wearable device.

In some embodiments, control module 18 and/or external computer processor 28 are configured to automatically derive one or more of the activity and/or mood data (step 56). For example, the control module 18 may derive a current activity state (e.g., eating, lying down, sleeping, walking, running, exercising, etc.) and/or a recent activity state of the subject based on data received from the accelerometer and/or PPG sensor. Alternatively or additionally, control module 18 may derive the current emotional state (e.g., tension, relaxation, etc.) and/or the recent emotional state of the subject based on data received from PPG sensor 11, accelerometer 13, and/or ECG sensor 16.

In some embodiments, the control module 18 is configured to receive the time of day and correlate it with measured values and/or other data, as described in this and the preceding paragraphs. In some embodiments, in this manner, the control module 18 is configured to build a database of how the subject's activities, emotional states, dietary states, and/or physiological parameters typically change during the day. In some embodiments, the control module 18 is configured to measure and/or receive input indicative of a hormonal status, symptoms (such as chest discomfort), blood-related parameters (e.g., anemia indication, B12 level, folate level, etc.) of the subject. Thus, in some embodiments, the control module 18 is configured to build a database that stores (step 64) the subject's active state, emotional state, dietary state, and/or physiological parameters over time, e.g., over the course of an hour, day, week, month, year, for example, in the memory storage device 18 a. In some embodiments, the control module 18 is configured to measure and/or receive inputs indicative of hormonal status, symptoms (such as chest discomfort, palpitations, heart jump-as described above), blood-related parameters (e.g., indications of anemia, iron deficiency, ferritin deficiency, B12 levels, leaf levels, etc.) of the subject.

In some embodiments, in step 60, control module 18 processes the received data to determine and/or predict that the subject is currently experiencing an arrhythmia-related event, such as AF, based on, for example, the subject's ECG signals and/or additional data. Alternatively or additionally, the control module 18 is configured to predict an upcoming arrhythmia-related event. For example, control module 18 may detect a rate of increase in Premature Atrial Contraction (PAC), which is interpreted as a precursor to a subject likely to experience AF in the near future. Alternatively or additionally, control module 18 may predict an upcoming arrhythmia-related event based on data related to the current activity state, emotional state, and/or dietary state of the subject in combination with additional physiological data. In some embodiments, control module 18 detects that the subject is currently experiencing an arrhythmia episode (such as occurrence of an atrial pre-systole, a ventricular pre-systole, an supraventricular tachycardia, and/or an atrial tachycardia). In some embodiments, control module 18 may be configured to determine an upcoming arrhythmia-related event based on a known recurrence history of the subject's arrhythmia-related event (e.g., at or about a specified time of day).

In some embodiments, control module 18 is configured to detect arrhythmia-related events as one or more of AF, atrial premature beat complex (APC/PAC), ventricular premature beat complex (VPC/PVC), supraventricular tachycardia (SVT), atrial Tachycardia (AT), atrial flutter, atrioventricular node reentry tachycardia (AVNRT), paroxysmal supraventricular tachycardia (PSVT), atrioventricular reentry tachycardia, pre-excitation syndrome, ventricular Tachycardia (VT), torsade pointes (TdP), long QT syndrome, cardiac conduction block, and/or sick sinus syndrome.

In some embodiments, based on the results of the detecting step 60, the control module 18 is configured to determine one or more therapy parameters including therapy session parameters and stimulation signal parameters in step 62. In some embodiments, the treatment parameters may include, but are not limited to:

the body part or the designated nerve is the target to be treated;

-number of treatment sessions;

-overall treatment session duration;

-a treatment session occasion;

-number and duration of on/off treatment session periods;

-total signal duration;

-signal waveforms (e.g. sinusoidal, triangular, rectangular and/or sawtooth waveforms);

Signal amplitude (e.g., maximum, minimum, medium, and/or average amplitude);

signal strength (e.g., maximum, minimum, medium, and/or average strength);

-a signal frequency;

signal pulse parameters (e.g. pulse duration and/or inter-pulse time interval) when the stimulation signal comprises a series of pulses; and/or

Synchronization of the signal with one or more other signals and/or reference activity (e.g. heart activity of the subject).

In some embodiments, step 62 may involve applying an intermittent stimulation signal (i.e., a voltage/current signal), that is, applying a series of electrical pulses (each electrical pulse being a stimulation signal of substantially short duration). In some embodiments, the time interval between successive electrical pulses and the shape (i.e., modulation or waveform) of each pulse may be controllably varied. In some embodiments, the stimulation pulse may be biphasic, that is, the positive voltage portion of the pulse is substantially immediately followed by the negative voltage portion of the pulse. In some embodiments, the area covered by the positive voltage (indicative of conductive charge) portion is substantially equal to the area covered by the negative portion, thereby preventing/minimizing the occurrence of electrolysis (which may be caused by the flow of current through the body tissue containing the fluid (in the target body portion) when the pulse width is sufficiently narrow (e.g., less than 1 msec).

In some embodiments, after determining the treatment parameters, control module 18 is configured to drive wearable device 10 to deliver and apply the determined treatment to the subject in step 62. As described above, typical treatment involves delivering electrical signals into the median nerve and/or ulnar nerve of a subject via wrist-facing electrodes 12a, 12 b.

In some embodiments, the control module 18 may be further configured to categorize and/or correlate current or predicted arrhythmia-related events or episodes as interrelated with parasympathetic or sympathetic status of the subject. In some embodiments, the control module 18 performs such classification based on the monitored and collected data received from the various sensors in step 58. Alternatively or additionally, control module 18 performs classification and correlation based on subject lifestyle related data and/or subject activity related data. For example, the control module 18 may be configured to derive whether the subject's parasympathetic tone is high and/or its sympathetic tone is low (or vice versa) based on the subject's current and/or recent emotional state, activity state, and/or dietary state.

In some embodiments, the control module 18 is configured to derive whether the subject's parasympathetic tone is high and/or its sympathetic tone is low (or vice versa) based on the subject's HRV, which is known to be indicative of the person's autonomic status. That said, it is often not possible to measure HRV of a subject in a reliable manner when the subject is experiencing an arrhythmia-related event episode. Thus, in some embodiments, to classify the episode, the control module 18 is configured to analyze the HRV of the subject for a given period of time (e.g., between 30 minutes and 1 minute) prior to the onset of the episode. In some embodiments, similar techniques are performed, but using heart rate and/or heart rate recovery of the subject as an alternative or in addition to HRV of the subject.

In some embodiments, the control module 18 is configured to derive whether the subject's parasympathetic tone is high and/or its sympathetic tone is low (or vice versa) based on the subject's ECG signal (e.g., the shape of the ECG signal and/or the regularity of the beats in the ECG signal).

In some embodiments, the control module 18 is configured to derive whether the parasympathetic tone of the subject is high and/or its sympathetic tone is low (or vice versa) based on parameters related to the premature atrial contractions and/or the atrial tachycardia episodes that the subject is currently experiencing and/or most recently experiencing. For example, control module 18 may determine whether the premature atrial contraction and/or the onset of atrial tachycardia occurred during exercise (indicating that they are correlated with excessive sympathetic tone) or during rest (indicating that they are correlated with excessive sympathetic tone).

Table 2 below summarizes various subject-related data points and parameters typically associated with sympathological or parasympathetic states:

table 2:

in some embodiments, when it is determined that the detected arrhythmia-related event correlates with parasympathetic status of the subject, the control module 18 is configured to determine that at least the stimulation signal frequency is to be set at a frequency between 40-50Hz (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 Hz).

In some embodiments, when it is determined that the detected arrhythmia-related event correlates with a sympathetic state (i.e., excessive sympathetic tone and/or parasympathetic or vagal tone decrease), the control module 18 is configured to determine a frequency (e.g., 1, 2, 3, 4, or 5 Hz) at which at least the stimulation signal frequency is to be set between 1-5 Hz.

Table 3 below summarizes the various detected upcoming or current arrhythmia-related events, their precursors, applicable signal parameters, and applicable treatment regimens.

Table 3:

in some embodiments, in step 64, after the treatment has been applied, the control module 18 is further configured to monitor and collect post-treatment data about the subject. In some embodiments, the post-treatment data may include some or all of the data items monitored and collected in step 58.

In some embodiments, in step 64, the control module 18 is configured to prompt the subject to record an ECG for a given period of time after the therapy has been applied. Alternatively or additionally, the control module 18 prompts the subject to take additional measurements. Further alternatively or additionally, the control module 18 drives one or more sensors to automatically detect additional physiological parameters of the subject. In some embodiments, the control module 18 is configured to receive additional data from other sensors, such as acoustic sensors, pressure sensors, optical sensors, and/or visual sensors, which may be disposed within the wearable device or external to the wearable device. In some embodiments, the control module 18 is configured to derive a post-treatment activity state of the subject (e.g., eating, lying down, sleeping, walking, running, exercising, etc.) based on data received from the accelerometer and/or PPG sensor. Alternatively or additionally, the control module 18 may derive a current post-treatment emotional state (e.g., tension, relaxation, etc.) of the subject based on data received from the accelerometer and/or PPG sensor. In some embodiments, the subject is prompted, e.g., via user interface 14, to enter information regarding their post-treatment lifestyle and/or activity. For example, the subject may be prompted to enter information regarding their emotional state (e.g., tension, relaxation, active emotion, bad emotion, etc.), symptoms (e.g., fatigue, chest distress, palpitations), and/or dietary state (e.g., hunger, current feeding, recent feeding, etc.). In some embodiments, the control module 18 is configured to receive the time of day and correlate it with measured values and/or other data, as described in this and the preceding paragraphs.

In some embodiments, in step 66, the control module 18 is configured to store the subject's self-reported data (e.g., subject ECG) into the respective treatments and correlate these data with subject characteristics, time of day, subject's activity status, subject's emotional status, subject's dietary status, subject's HRV, and the like. The database may include subject-specific data and derived correlations, as well as data and derived correlations relating to a group of subjects and/or all subjects who have been treated using such a system. In some embodiments, the data includes data related to the status of the subject (e.g., the frequency of occurrence of arrhythmia events) prior to having applied the treatment.

In some embodiments, such data may include, but is not limited to:

the time before the recurrence of AF,

until the time of recurrence of the premature atrial contraction,

general atrial/ventricular activity,

atrial fibrillation load, measured as the total time/percentage time of AF and sinus rhythm in a defined measurement period or the number of AF episodes in a predetermined time period,

the average length of time in an AF event,

the longest AF event is chosen to be the most severe,

Self-reporting of symptoms and activities, moods and dietary status of the subject,

prior treatment parameters for the treatment,

the number of treatments (during the day),

the duration of the treatment is chosen to be chosen,

-a parameter of the electrical signal,

subject personal parameters (e.g., age, sex, height, weight, average heart load).

In some embodiments, the clinical effect is analyzed based on changes in cardiac load, time until AF recurs, time until premature atrial contractions recur, and/or self-reporting of symptoms and activities, mood, and dietary status of the subject. In some embodiments, to determine the status and/or clinical effect of the subject, the control module 18 is configured to determine the heart load of the subject, which is typically determined based on: (a) number of episodes in a defined period of time, (b) length of each episode in a defined period of time, (c) percentage of time of AF in a defined period of time, and/or (d) severity of symptoms reported.

Typically, the results of the analysis performed in step 64 are then used as inputs in steps 60, 62 and/or 64. That is, when the subject is experiencing a clinical episode or is predicted to experience an episode, then in step 60, the subject's and/or other subjects responses to previous treatments are considered in addition to analyzing current data or recently acquired subject-related data. Similarly, in step 64, in order to determine which treatment parameters to apply to the subject, the subject's and/or other subjects' responses to previous treatments are considered in addition to analyzing current data or recently acquired subject-related data, e.g., using artificial intelligence and/or machine learning algorithms.

In some embodiments, in performing the steps of the flowchart shown in FIG. 4, the system utilizes a combination of the following data types:

-a target subject physiological parameter, generally comprising: heart rate, heart rate reserve, heart rate recovery, HRV, atrial extra-systole, ventricular extra-systole, AF, atrial tachycardia, exercise, sleep, activity.

-subjective subject parameters, which generally comprise: subject symptoms, dietary status, exercise, hormonal status, stress level, hydration level.

-an externally measured physiological parameter, which generally comprises: blood examination (e.g. TNF, IL-6, CRP), blood pressure.

-electrical stimulation parameters: pulse waveform, pulse frequency, pulse intensity, pulse interval, treatment duration, and treatment regimen.

-a therapeutic effect, generally comprising: objective data (such as ECG, HRV, heart rate recovery, heart rate, PPG) and subjective data (such as reports of subject symptoms and status).

In some embodiments, the system incorporates additional data into the data analysis, such as a historical information database (including their treatments and therapeutic effects) related to subjects who have been treated using the system, animal studies, DRGs, vagal and/or stellate recordings, scientific literature, and/or clinical knowledge.

With respect to the treatments described herein, it should be noted that in some cases, these treatments are used as an adjunct to conventional treatments (e.g., ablation). It should also be noted that for a given subject, the duration and/or frequency of treatment will generally decrease over time, as the system trains the subject's nervous system to self-regulate, and/or due to changes in the subject's condition or other parameters.

Experimental results

Referring now to fig. 5A-5D, experimental results of stimulation therapy performed on AF subjects according to some applications of the present invention are shown.

Referring to fig. 5A, a chart showing AF recurrence in a cohort of 14 AF subjects treated with the treatment described herein (using a signal with a frequency of 40-50 Hz). The recurrence rate of AF in subjects treated as described herein is indicated by the dashed line. For comparison, the recurrence rate of subjects receiving standard medical care after cardioversion is shown by the solid line. The data sources shown in solid lines are as follows:

-a predictor of arrhythmia recurrence in AF-only subjects. European space (2008) 10,9-14.

Early recurrence of AF after cardioversion. JACC volume 31, phase 1. 167-73 in 1 month of 1998.

Early AF of recent onset or delayed cardioversion. N Engl J med.2019, 7 months 25; 381 (4): 386-387.

Prevention of AF after cardioversion: PAFAC test results. European journal of heart (2004) 25, 1385-1394.

For the dashed line shown in fig. 5A, data were collected from two family clinics at the israeli center from month 6 of 2018 to month 9 of 2020 and analyzed as retrospective open-label case registrations. The cohort consisted of 14 men and women, aged 18 years or older, symptomatic and ECG recorded, recent onset Atrial Fibrillation (AF) for less than 48 hours. As described herein, neuromodulation therapy was performed weekly using the wearable device for 10 weeks. Each session/session was performed for 20 minutes. After 10 weeks, the treatment frequency was reduced to one course of treatment every two weeks, then to once a month for the remainder of the follow-up period. Subjects received up to two years of follow-up. During the follow-up period, 3 subjects developed a recurrence of atrial fibrillation with symptomatic and ECG recordings. These occurred on weeks 8, 28 and 42, respectively, in three different subjects. The total recurrence rate was 7.1% (1/14) at 6 months of follow-up, and 21.4% (3/14) at 1 year of follow-up. Quality of life assessed by the AFEQT (effect of AF on quality of life) questionnaire was submitted by 13 participants and showed significant improvement in AF-related symptoms (26.1%), daily activities (14.7%), mental problems (37%) and total score (23.4%), as shown in table 4 below.

Table 4:

fig. 5D shows ECG signals for a 65 year old male with AF before the treatment described herein is applied (panel a) and after the 25 minute treatment described herein is applied (panel B). It can be observed that the subject suffered multiple ventricular extra-systoles (indicated by the circled portion of the ECG signal) prior to treatment. After treatment, the subject no longer developed ventricular extra-systoles.

The inventors performed an experiment comprising a cohort of 48 patients who received a total of 136 neuromodulation treatments according to various aspects of the present disclosure, as described above.

The patient exhibited a low SDNN (standard deviation of NN interval) of <36ms, which indicated an increased risk of atrial fibrillation (e.g., "Cardiac Autonomic Dysfunction and Incidence of Atrial Fibrillation: results From 20Years Follow-Up (cardiac autonomic dysfunction and atrial fibrillation incidence: 20Years Follow-Up)", J Am Coll Cardiol,2017, 24 th 1 month; 69 (3): 291-299). Low SDNN is detected prior to providing treatment and is determined to indicate that the subject's autonomic nervous system is in a sympatholytic state. Thus, the treatment comprises delivering to the subject a stimulation signal having a frequency between 1-5 Hz. The experimental results are summarized in table 5 below. Fig. 6 is a graph showing experimental results. It can be seen that the mean SDNN value for all patients increased by 22% after treatment.

Table 5:

parameters (parameters)	Before averaging	After averaging	% change	p value
					HR	67.42	64.18	4.8	<0.001
SDNN (millisecond)	35.65	43.50	22.02	<0.001
					rMSSD (millisecond)	30.14	40.73	35.11	<0.001
LF	301.58	394.64	30.86	0.014
					HF	175.05	239.38	36.75	<0.001
VLF	349.26	431.46	23.54	0.09
					Ln LF	5.07	5.40	6.5	<0.001
LH/HF	2.54	2.70	6.24	0.595

As described above, the electrodes 12a, 12b are generally configured to be placed on the skin of the subject's wrist near the subject's ulnar nerve and/or the subject's median nerve. Typically, the electrical stimulation signal is driven into the nerve via the electrodes, and the electrical stimulation signal is configured to reduce the occurrence of AF and/or arrhythmia events. In some embodiments, the electrical analog signal has parameters as described above. The inventors of the present application have found that when the electrodes are properly positioned relative to the nerve and the stimulation parameters are set, such as to produce a desired clinical effect, the subject typically experiences a sensation of radiation from near the electrodes and along the neural pathway (e.g., in the subject's wrist, hand, and/or finger). In particular, when the intensity of the electrical analog signal is high enough to produce the desired clinical result, the subject typically perceives a sensation that emanates from near the electrode and along the neural pathway. However, it is generally undesirable for the electrical stimulation signal to elicit a motor response, which may occur if the intensity of the electrical stimulation signal is too high. For example, in some cases, the electrical stimulation signal may cause involuntary movement of a portion of the subject's body in the vicinity of the electrode (e.g., in the subject's wrist, hand, and/or hand). In view of the above, in some embodiments, the control module and/or a different one of the computing devices 28 described herein is configured to receive input from the subject indicating a response of the subject's body in the vicinity of the electrode to the electrical stimulation signal. For example, control module 18 may receive input from a subject via user interface 14 and/or via smartphone 30, tablet 32, and/or personal computer 34 (as shown in fig. 1A). Typically, the control module 18 sets the intensity of the electrical stimulation signal such that the electrical stimulation signal causes a sensation in the vicinity of the electrode (e.g., a sensation that begins in the vicinity of the electrode and radiates along the neural pathway as described above), but does not result in involuntary movement of a portion of the subject's body in the vicinity of the electrode. For example, control module 18 may increase the intensity of the electrical stimulation signal in response to receiving an input indicating that the electrical stimulation signal does not cause any sensation in the vicinity of the electrode, and control module 18 may decrease the intensity of the electrical stimulation signal in response to receiving an input indicating that the electrical stimulation signal causes involuntary movement of a portion of the subject's body in the vicinity of the electrode.

Another phenomenon found by the inventors is that when an electrical analog signal is applied at a given voltage, the current of the signal tends to be higher when the electrode is properly positioned relative to the ulnar nerve and/or median nerve. It should be noted that this is the case even when the electrodes are in good contact with the skin of the subject. That is, even when the electrode is in good contact with the skin, a change in current is observed, and when the electrode is placed appropriately with respect to the ulnar nerve and/or median nerve, the current of the signal tends to be higher. This suggests that this phenomenon is independent of the impedance due to improper contact between the electrode and the skin.

For the treatment of AF and/or arrhythmic diseases, it is desirable that the electrical stimulation signal is radiated along the ulnar nerve and/or the median nerve (both close to the skin surface). The inventors have shown that when the electrode is properly positioned relative to the nerve, the current is higher due to the electrical stimulation signal radiating along the nerve, and that the current is lower when the electrode is not properly positioned relative to the nerve. It should be noted that a similar phenomenon can be seen when a stimulus signal is applied at a given current. That is, when an electrical analog signal is applied at a given current, the voltage of the signal tends to be low when the electrode is properly positioned relative to the ulnar nerve and/or median nerve, even when the electrode is in good contact with the subject's skin.

In view of the above, in some embodiments, control module 18 and/or a different one of computing devices 28 described herein is configured to drive electrical stimulation signals into the ulnar nerve and/or median nerve via the electrodes at a given voltage. When the electrodes are in good contact with the skin of the subject's wrist, the control module 18 detects the current of the electrical stimulation signal, and in response to the current being below a threshold, the control module 18 generates an output indicating that at least one of the electrodes should be moved (e.g., indicating that at least one of the electrodes should be moved closer to the selected nerve). For example, control module 18 may generate such output to the subject via a user interface and/or via smartphone 30, tablet device 32, and/or personal computer 34. In some embodiments, control module 18 and/or a different one of the computing devices described herein is configured to drive the electrical stimulation signals into the ulnar nerve and/or median nerve via the electrodes at a given current. When the electrodes are in good contact with the skin of the subject's wrist, the control module 18 detects the voltage of the electrical stimulation signal, and in response to the voltage being above a threshold, the control module 18 generates an output indicating that at least one of the electrodes should be moved (e.g., indicating that at least one of the electrodes should be moved closer to the selected nerve). For example, control module 18 may generate such output to the subject via user interface 14 and/or via smartphone 30, tablet device 32, and/or personal computer 34.

As described above, in some embodiments, the control module 18 and/or a different one of the computing devices described herein is configured to be currently experiencing AF by the subject, currently experiencing an arrhythmia episode by the subject, predicted to be experiencing AF, and/or predicted to be experiencing an arrhythmia episode based on analyzing the ECG signal of the subject. In some embodiments, the control module 18 is configured to classify AF and/or arrhythmia events as one or more of atrial premature beat complex (APC/PAC), ventricular premature beat complex (VPC/PVC), supraventricular tachycardia (SVT), atrial Tachycardia (AT), atrial flutter, atrioventricular node reentry tachycardia (AVNRT), paroxysmal supraventricular tachycardia (PSVT), atrioventricular reentry tachycardia, pre-excitation syndrome, ventricular Tachycardia (VT), torsade pointes (Torsades de pointes), long QT syndrome, cardiac conduction block, and/or sick sinus syndrome. In some embodiments, the control module 18 is configured to derive whether the subject's parasympathetic tone is high and/or its sympathetic tone is low (or vice versa) based on the subject's ECG signal.

The present invention may be a system, method and/or computer program product. The computer program product may include a computer readable storage medium (or media) having computer readable program instructions thereon for causing a processor to perform the various aspects of the invention.

A computer readable storage medium may be a tangible device that can retain and store instructions for use by an instruction execution device. The computer readable storage medium may be, for example, but not limited to, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of the foregoing. A non-exhaustive list of more specific examples of the computer readable storage medium would include the following: portable computer diskette, hard disk, random Access Memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EPROM or flash memory), static Random Access Memory (SRAM), portable compact disc read-only memory (CD-ROM), digital Versatile Disc (DVD), memory stick, floppy disk, mechanical coding device having instructions recorded thereon, and any suitable combination of the foregoing. A computer-readable storage medium as used herein should not itself be construed as a transitory signal such as a radio wave or other freely propagating electromagnetic wave, an electromagnetic wave propagating through a waveguide or other transmission medium (e.g., an optical pulse through a fiber optic cable), or an electrical signal transmitted through a wire. Rather, computer-readable storage media are non-transitory (i.e., non-volatile) media.

The computer readable program instructions described herein may be downloaded from a computer readable storage medium to a corresponding computing/processing device or over a network (e.g., the internet, a local area network, a wide area network, and/or a wireless network) to an external computer or external storage device. The network may include copper transmission cables, optical transmission fibers, wireless transmissions, routers, firewalls, switches, gateway computers and/or edge servers. The network adapter card or network interface in each computing/processing device receives computer readable program instructions from the network and forwards the computer readable program instructions for storage in a computer readable storage medium within the respective computing/processing device.

Computer readable program instructions for performing the operations of the present invention may be assembly instructions, instruction Set Architecture (ISA) instructions, machine-related instructions, microcode, firmware instructions, state setting data, or source or object code written in any combination of one or more programming languages, including an object oriented programming language such as Java, smalltalk, C ++ or the like and conventional procedural programming languages, such as the "C" programming language or similar programming languages. The computer readable program instructions may be executed entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a Local Area Network (LAN) or a Wide Area Network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet service provider). In some embodiments, electronic circuitry, including, for example, programmable logic circuitry, field Programmable Gate Arrays (FPGAs), or Programmable Logic Arrays (PLAs), may execute computer-readable program instructions by utilizing state information of the computer-readable program instructions to personalize the electronic circuitry, thereby performing aspects of the present invention. In some embodiments, electronic circuitry, including, for example, an Application Specific Integrated Circuit (ASIC), may incorporate computer readable program instructions that already exist at the time of manufacture, such that the ASIC is configured to execute these instructions without programming.

Aspects of the present invention are described herein with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems) and computer program products according to embodiments of the invention. It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer-readable program instructions.

These computer readable program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks. These computer readable program instructions may also be stored in a computer readable storage medium that can direct a computer, programmable data processing apparatus, and/or other devices to function in a particular manner, such that the computer readable storage medium having the instructions stored therein includes an article of manufacture including instructions which implement the function/act specified in the flowchart and/or block diagram block or blocks.

The computer readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer, other programmable apparatus or other devices implement the functions/acts specified in the flowchart and/or block diagram block or blocks.

The flowcharts and block diagrams in the figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods and computer program products according to various embodiments of the present invention. In this regard, each block in the flowchart or block diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s). It will also be noted that each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration, can be implemented by special purpose hardware-based systems which perform the specified functions or acts, or combinations of special purpose hardware and computer instructions.

In the description and claims, when describing a numerical value, each of the terms "substantially", "essentially" and forms thereof means a deviation of up to 20% (i.e., ±20%) from the value. Similarly, when such a term describes a numerical range, it means a broader range up to 20% -10% above and 10% below that explicit range.

In the description, any given range of values should be considered to have specifically disclosed all possible subranges and individual values within the range, such that each such subrange and individual value constitutes an embodiment of the invention. This applies regardless of the extent. For example, a description of an integer range from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within the range, e.g., 1, 4, and 6. Similarly, descriptions of fractional ranges (e.g., 0.6 to 1.1) should be considered to specifically disclose subranges such as from 0.6 to 0.9, from 0.7 to 1.1, from 0.9 to 1, from 0.8 to 0.9, from 0.6 to 1.1, from 1 to 1.1, etc., as well as individual numbers within the range, e.g., 0.7, 1, and 1.1.

The description of the various embodiments of the present application has been presented for purposes of illustration and description, but is not intended to be exhaustive or limited to the precise description. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles of the embodiments, the practical application, or the technical improvement of commercially available technology, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.

In the description and claims of the present application, each of the words "comprising," "including," and "having" and forms thereof are not necessarily limited to members of the list with which the words may be associated.

If there is a discrepancy between the specification and any document incorporated by reference or otherwise relied upon, the specification controls the present specification.

Claims

1. A system, comprising:

a control module;

a neural stimulation unit operatively controlled by the control module and configured to generate an electrical stimulation signal having a frequency between 40-50 Hz; and

at least two electrodes configured to be positioned in simultaneous transdermal contact with an inner surface of a wrist of a subject and proximate to a median nerve of the subject, wherein each of the at least two electrodes is connected to the nerve stimulation unit for delivering generated electrical stimulation signals from the nerve stimulation unit to the subject,

Wherein the electrical stimulation signal is configured to apply neuromodulation therapy to the subject to reduce the occurrence of a arrhythmia-related condition in the subject.

2. The system of claim 1, wherein the control module is configured to operate the neural stimulation unit to generate the electrical stimulation signal according to a predetermined schedule, and wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes.

3. The system of any of claims 1 or 2, wherein the control module is configured to receive as input data indicative of at least one parameter selected from the group of parameters consisting of: an activity state parameter of the subject, a diet state parameter of the subject, and an emotional state parameter of the subject.

4. The system of claim 3, wherein the control module is configured to predict a current or impending occurrence of the arrhythmia-related condition regarding the subject based on the data, and to operate the neural stimulation unit to generate the electrical stimulation signal based at least in part on the prediction, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes.

5. The system of any one of claims 3 or 4, wherein the:

(i) The activity state parameter of the subject indicates that the subject is in at least one of the following states: eating, lying down, sleeping, walking, running, exercising or driving;

(ii) The dietary status parameter of the subject indicates that the subject is in at least one of the following states: starvation, current eating, or recent eating; and

(iii) The emotional state parameter of the subject indicates that the subject is in at least one of the following states: tension, relaxation, emotional aggression, depression, anxiety, or trauma.

6. The system of any of claims 1-5, wherein the control module is further configured to receive as additional input data indicative of at least one additional parameter about the subject, the additional parameter selected from the group consisting of: fatigue, chest distress, palpitations, dizziness, fainting, headache, shortness of breath, chest "empty" sensations, tachycardia or tremors, heart jumping, throat pressure, cold or chills, dehydration, blood related parameters, anemia diagnosis, digestive related symptoms, insomnia and hormonal data.

7. The system of any of claims 4-6, wherein the predicting is based at least in part on correlating at least one of the parameters including the data in the subject with an occurrence of the arrhythmia-related condition, and wherein the correlating is based on current and historical information associated with the occurrence of the arrhythmia-related condition in the subject.

8. The system of any of claims 1-7, wherein the control module is further configured to receive a cardiac activity signal of the subject as an additional input.

9. The system of claim 8, wherein the control module is further configured to process the cardiac activity signal to derive one or more cardiac activity related parameters selected from the group consisting of: heart Rate Variability (HRV), heart rate recovery, heart rate reserve, atrial extra-systole (PAC), ventricular extra-systole, atrial tachycardia, RR intervals, average interval between normal heartbeats (AVNN), standard deviation of NN intervals (SDNN), root mean square of continuous differences between normal heartbeats (rMSSD), pNN50, low frequency activity (LF), and high frequency activity (HF).

10. The system of any of claims 8 or 9, wherein the control module is further configured to detect a current or impending occurrence of the arrhythmia-related condition regarding the subject based on the cardiac activity signal, and operate the neural stimulation unit to generate the electrical stimulation signal based at least in part on the detection, and wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes.

11. The system of any of claims 1-10, wherein the control module is further configured to determine that the subject's autonomic nervous system is in a sympathetic or parasympathetic state.

12. The system of claim 11, wherein when the autonomic nervous system of the subject is in a sympathological state, the control module is configured to operate the neural stimulation unit to generate the electrical stimulation signal at a frequency between 1-5 Hz.

13. The system of any of claims 1-12, further comprising at least one of: electrocardiograph (ECG) sensors, photoplethysmogram (PPG) sensors, and accelerometers.

14. The system of any of claims 1-13, wherein the system is at least partially housed within a wearable device configured to be worn by the subject.

15. The system of claim 14, wherein the wearable device comprises a wristband configured to be worn around the subject's wrist such that the at least two electrodes are each positioned along their longitudinal axis proximate to and substantially parallel to a longitudinal axis of the median nerve.

16. The system of any of claims 1-15, wherein the arrhythmia-related condition is one or more of: atrial Fibrillation (AF), atrial premature beat complex (PAC), ventricular premature beat complex (PVC), supraventricular tachycardia (SVT), atrial Tachycardia (AT), atrial flutter, atrioventricular node reentry tachycardia (AVNRT), paroxysmal supraventricular tachycardia (PSVT), atrioventricular reentry tachycardia, pre-excitation syndrome, ventricular Tachycardia (VT), torsades de pointes (TdP), long QT syndrome, cardiac arrest and sick sinus syndrome.

17. The system of any of claims 1-16, wherein the control module is further configured to measure a current associated with the electrical stimulation signal between the at least two electrodes, and determine that the positioning of the at least two electrodes relative to the inner surface of the subject's wrist is incorrect when the measured current is below a predetermined baseline value.

18. The system of claim 17, wherein the predetermined baseline value is determined by measuring a current associated with the electrical stimulation signal between the at least two electrodes when the at least two electrodes are each positioned along their longitudinal axes proximate to and substantially parallel to a longitudinal axis of the median nerve.

19. A method, comprising:

there is provided a system comprising:

the control module is used for controlling the control module,

a neural stimulation unit operatively controlled by the control module and configured to generate an electrical stimulation signal having a frequency between 40-50Hz, and

wherein the electrical stimulation signal is configured to apply neuromodulation therapy to the subject to reduce the occurrence of a arrhythmia-related condition in the subject; and

The at least two electrodes are placed in simultaneous transdermal contact with an inner surface of the wrist of the subject such that each of the at least two electrodes is positioned along its longitudinal axis proximate to and substantially parallel to a longitudinal axis of the median nerve.

20. The method of claim 19, further comprising operating the neural stimulation unit according to a predetermined schedule to generate the electrical stimulation signal, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes.

21. The method of any of claims 19 or 20, wherein the control module is configured to receive as input data indicative of at least one parameter selected from the group of parameters consisting of: an activity state parameter of the subject, a diet state parameter of the subject, and an emotional state parameter of the subject.

22. The method of claim 21, further comprising: predicting a current or impending occurrence of the arrhythmia-related condition with respect to the subject based on the data; and operating the neural stimulation unit to generate the electrical stimulation signal based at least in part on the prediction, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes.

23. The method of any of claims 19-22, wherein the control module is further configured to receive as additional input data indicative of at least one additional parameter about the subject, the at least one additional parameter selected from the group consisting of: fatigue, chest distress, palpitations, dizziness, fainting, headache, shortness of breath, chest "empty" sensations, tachycardia or tremors, heart jumping, throat pressure, cold or chills, dehydration, blood related parameters, anemia diagnosis, digestive related symptoms, insomnia and hormonal data.

24. The method of any of claims 19-23, wherein the predicting is based at least in part on correlating at least one of the parameters comprising the data in the subject with the occurrence of the arrhythmia-related condition, and wherein the correlating is based on current and historical information associated with the occurrence of the arrhythmia-related condition in the subject.

25. The method of any of claims 19-24, wherein the control module is further configured to receive a cardiac activity signal of the subject as an additional input.

26. The method of claim 25, wherein the control module is further configured to process the cardiac activity signal to derive one or more cardiac activity related parameters selected from the group consisting of: heart Rate Variability (HRV), heart rate recovery, heart rate reserve, atrial extra-systole (PAC), ventricular extra-systole, atrial tachycardia, RR intervals, average interval between normal heartbeats (AVNN), standard deviation of NN intervals (SDNN), root mean square of continuous differences between normal heartbeats (rMSSD), pNN50, low frequency activity (LF), and high frequency activity (HF).

27. The method of any one of claims 25 or 26, further comprising: detecting a current or impending occurrence of the arrhythmia-related condition of the subject based on the one or more cardiac activity signals; and operating the neural stimulation unit to generate the electrical stimulation signal based at least in part on the detecting, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes.

28. The method of any of claims 19-27, wherein the control module is further configured to determine that the subject's autonomic nervous system is in a sympathetic or parasympathetic state.

29. The method of claim 28, wherein when the autonomic nervous system of the subject is in a sympathological state, the control module is configured to operate the neural stimulation unit to generate the electrical stimulation signal at a frequency between 1-5 Hz.

30. The method of any of claims 19-29, wherein the system further comprises at least one of: electrocardiograph (ECG) sensors, photoplethysmogram (PPG) sensors, and accelerometers.

31. The method of any of claims 19-30, wherein the system is at least partially housed within a wearable device configured to be worn by the subject, and wherein the wearable device comprises a wristband configured to be worn around a wrist of the subject such that the at least two electrodes are each positioned along their longitudinal axes proximate to a longitudinal axis of the median nerve and substantially parallel to the longitudinal axis of the median nerve.

32. The method of any of claims 19-31, wherein the arrhythmia-related condition is one or more of: atrial Fibrillation (AF), atrial premature beat complex (PAC), ventricular premature beat complex (PVC), supraventricular tachycardia (SVT), atrial Tachycardia (AT), atrial flutter, atrioventricular node reentry tachycardia (AVNRT), paroxysmal supraventricular tachycardia (PSVT), atrioventricular reentry tachycardia, pre-excitation syndrome, ventricular Tachycardia (VT), torsades de pointes (TdP), long QT syndrome, cardiac arrest and sick sinus syndrome.

33. The method of any of claims 19-32, wherein the control module is further configured to measure a current associated with the electrical stimulation signal between the at least two electrodes, and determine that the positioning of the at least two electrodes relative to the inner surface of the wrist of the subject is incorrect when the measured current is below a predetermined baseline value.

34. The method of claim 33, wherein the predetermined baseline value is determined by measuring a current associated with the electrical stimulation signal between the at least two electrodes when the at least two electrodes are each positioned along their longitudinal axes proximate to and substantially parallel to a longitudinal axis of the median nerve.

35. A system, comprising:

a control module;

a neural stimulation unit operably controlled by the control module and configured to generate an electrical stimulation signal; and

Wherein the control module is configured to:

receiving as input a cardiac activity signal of the subject,

detecting a current or impending arrhythmia-related condition relating to the subject based on the cardiac activity signal, and

operating the neural stimulation unit to generate the electrical stimulation signal having a frequency between 40-50Hz, wherein the generated electrical stimulation signal is delivered from the neural stimulation unit to the subject via the at least two electrodes, and

wherein the electrical stimulation signal is configured to apply neuromodulation therapy to the subject to reduce the occurrence of the arrhythmia-related condition in the subject.

36. The system of claim 35, wherein the control module is configured to detect the impending occurrence of the arrhythmia-related condition based at least in part on detection of at least one of atrial premature composite (PAC) and ventricular premature composite (PVC) in the cardiac activity signal.

37. The system of claim 36, wherein the detecting is based on measuring a percentage increase in the one of PAC and PVC in the cardiac activity signal relative to a baseline measurement of the subject.

38. The system of any of claims 35-37, further comprising at least one of: electrocardiograph (ECG) sensors, photoplethysmogram (PPG) sensors, and accelerometers.

39. The system of any of claims 35-38, wherein the control module is further configured to process the cardiac activity signal to derive one or more cardiac activity related parameters selected from the group consisting of: heart Rate Variability (HRV), heart rate recovery, heart rate reserve, atrial extra-systole (PAC), ventricular extra-systole, atrial tachycardia, RR intervals, average interval between normal heartbeats (AVNN), standard deviation of NN intervals (SDNN), root mean square of continuous differences between normal heartbeats (rMSSD), pNN50, low frequency activity (LF), and high frequency activity (HF).

40. The system of claim 39, wherein the detecting is based at least in part on the one or more cardiac activity related parameters.

41. The system of any of claims 35-40, wherein the control module is further configured to receive data indicative of at least one additional parameter as an additional input, the at least one additional parameter selected from the group consisting of: an active state of the subject, a dietary state of the subject, and an emotional state of the subject.

42. The system of any one of claims 35-41, wherein the control module is further configured to determine that the subject's autonomic nervous system is in a sympathetic or parasympathetic state.

43. The system of claim 42, wherein when the autonomic nervous system of the subject is in a sympathological state, the control module is configured to operate the neural stimulation unit to generate the electrical stimulation signal at a frequency between 1-5 Hz.

44. The system of any of claims 35-43, wherein the system is housed within a wearable device configured to be worn by a subject, and wherein the wearable device comprises a wristband configured to be worn around a wrist of the subject such that the at least two electrodes are each positioned along their longitudinal axes proximate to and substantially parallel to a longitudinal axis of the median nerve.

45. The system of any one of claims 35-44, wherein the arrhythmia-related condition is one or more of: atrial Fibrillation (AF), atrial premature beat complex (PAC), ventricular premature beat complex (PVC), supraventricular tachycardia (SVT), atrial Tachycardia (AT), atrial flutter, atrioventricular node reentry tachycardia (AVNRT), paroxysmal supraventricular tachycardia (PSVT), atrioventricular reentry tachycardia, pre-excitation syndrome, ventricular Tachycardia (VT), torsades de pointes (TdP), long QT syndrome, cardiac arrest and sick sinus syndrome.

46. The system of any one of claims 35-45, wherein the control module is further configured to measure a current associated with the electrical stimulation signal between the at least two electrodes, and determine that the positioning of the at least two electrodes relative to the inner surface of the wrist of the subject is incorrect when the measured current is below a predetermined baseline value.

47. The system of claim 46, wherein the predetermined baseline value is determined by measuring a current associated with the electrical stimulation signal between the at least two electrodes when the at least two electrodes are each positioned along their longitudinal axes proximate to and substantially parallel to a longitudinal axis of the median nerve.

48. A method, comprising:

there is provided a system comprising:

a control module;

Wherein the control module is configured to:

receiving as input a cardiac activity signal of the subject,

wherein the electrical stimulation signal is configured to apply neuromodulation therapy to the subject,

to reduce the occurrence of the arrhythmia-related condition in the subject; and

the at least two electrodes are placed in simultaneous transdermal contact with an inner surface of the wrist of the subject such that each of the at least two electrodes is positioned adjacent and substantially parallel to a longitudinal axis of the median nerve along its longitudinal axis.

49. The method of claim 48, wherein the control module is configured to detect the impending occurrence of the arrhythmia-related condition based at least in part on detecting at least one of atrial premature composite (PAC) and ventricular premature composite (PVC) in the cardiac activity signal.

50. The method of any one of claims 48 or 49, further comprising at least one of: electrocardiograph (ECG) sensors, photoplethysmogram (PPG) sensors, and accelerometers.

51. The method of any of claims 48-50, wherein the control module is further configured to process the cardiac activity signal to derive one or more cardiac activity related parameters selected from the group consisting of: heart Rate Variability (HRV), heart rate recovery, heart rate reserve, atrial extra-systole (PAC), ventricular extra-systole, atrial tachycardia, RR intervals, average interval between normal heartbeats (AVNN), standard deviation of NN intervals (SDNN), root mean square of continuous differences between normal heartbeats (rMSSD), pNN50, low frequency activity (LF), and high frequency activity (HF).

52. The method of any of claims 48-51, wherein the control module is further configured to receive data indicative of at least one additional parameter as an additional input, the at least one additional parameter selected from the group consisting of: an active state of the subject, a dietary state of the subject, and an emotional state of the subject.

53. The method of any one of claims 48-52, wherein the control module is further configured to determine that the subject's autonomic nervous system is in a sympathetic or parasympathetic state, and wherein when the subject's autonomic nervous system is in a sympathetic state, the control module is configured to operate the neural stimulation unit to generate the electrical stimulation signal at a frequency between 1-5 Hz.

54. The method of any of claims 48-53, wherein the system is housed within a wearable device configured to be worn by a subject, and wherein the wearable device comprises a wristband configured to be worn around a wrist of the subject such that the at least two electrodes are each positioned along their longitudinal axes proximate and substantially parallel to a longitudinal axis of the median nerve.

55. The method of any one of claims 48-54, wherein the arrhythmia-related condition is one or more of: atrial Fibrillation (AF), atrial premature beat complex (PAC), ventricular premature beat complex (PVC), supraventricular tachycardia (SVT), atrial Tachycardia (AT), atrial flutter, atrioventricular node reentry tachycardia (AVNRT), paroxysmal supraventricular tachycardia (PSVT), atrioventricular reentry tachycardia, pre-excitation syndrome, ventricular Tachycardia (VT), torsades de pointes (TdP), long QT syndrome, cardiac arrest and sick sinus syndrome.