Heart rate regulation and control system based on focused ultrasound and application of heart rate regulation and control system

Abstract

The invention relates to the field of treatment ultrasound, in particular to a heart rate regulation and control system based on focused ultrasound and application of the heart rate regulation and control system. The heart rate regulation and control system based on focused ultrasound comprises an ultrasonic stimulation module, a central control module and an electrocardiosignal acquisition module, the ultrasonic stimulation module is in communication connection with the central control module, and the electrocardiosignal acquisition module is in communication connection with the central control module. The heart rate regulation and control system based on focused ultrasound provided by the invention is controlled by the multi-degree-of-freedom mobile platform to noninvasively convey ultrasonic energy to a heart target region, so that the following effects are achieved: 1) the heart rate can be noninvasively and safely regulated; 2) the system is simple to operate; 3) the heart rate regulation and control effect is high in real-time performance; and 4) the heart rate regulation and control effect is obvious, and the heart rate can be increased by 10-40%.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of therapeutic ultrasound, in particular to a focused ultrasound-based heart rate regulation system and its use. BACKGROUND

[0002] Both bradycardia and elevated resting heart rate are considered risk factors for cardiovascular diseases. Restoring heart rate to normal levels not only improves the quality of life for patients with cardiovascular diseases, but also plays a key role in the prevention and management of cardiovascular diseases. Bradycardia is mainly caused by sick sinus syndrome and atrioventricular block. The current main treatment methods include drug therapy and cardiac pacemaker implantation. Drug therapy, such as the use of atropine, can temporarily increase heart rate, but long-term use of drugs can lead to side effects and drug resistance. Cardiac pacemaker implantation is a more durable solution, which uses electronic devices to send regular electrical impulses to the heart to maintain normal heart rate. However, cardiac pacemaker implantation is an invasive surgery, which has the defects of invasiveness, high risk of infection, and the need for regular maintenance. These shortcomings limit the universal applicability of these traditional treatment methods and the acceptance of patients. Therefore, the limitations of existing treatment methods have prompted the medical community to seek new treatment solutions, especially the growing demand for non-invasive heart rate regulation technology. Non-invasive heart rate regulation technology aims to provide a safe, effective, and convenient treatment option that can avoid the side effects and drug resistance of drug therapy, and eliminate the invasive risks and related complications of cardiac pacemaker implantation, providing a more ideal treatment solution for patients with bradycardia. SUMMARY

[0003] In view of the above-mentioned shortcomings of the prior art, the purpose of the present application is to provide a focused ultrasound-based heart rate regulation system and its use, which solves the problems of invasiveness, large side effects, and high drug resistance in the prior art.

[0004] To achieve the above-mentioned purposes and other related purposes, the present application provides a focused ultrasound-based heart rate regulation system, which comprises an ultrasonic stimulation module for ultrasonic stimulation in different ultrasonic stimulation modes according to control instructions to achieve heart rate regulation; an electrocardiogram signal acquisition module for monitoring and storing electrocardiogram signals and sending monitored electrocardiogram data; and a central control module, which is in communication with the ultrasonic stimulation module and the electrocardiogram signal acquisition module, receives the electrocardiogram data sent by the electrocardiogram signal acquisition module, calculates heart rate indicators, and switches different ultrasonic stimulation modes according to the changes in heart rate, and outputs control instructions to the ultrasonic stimulation module.

[0005] Preferably, the ultrasonic stimulation module comprises a signal generator in communication with the central control module for generating ultrasonic stimulation waveforms under the control of the central control module.

[0006] A power amplifier, which is in communication connection with the signal generator, is used to amplify the output signal of the signal generator and drive the focused ultrasound transducer to work;

[0007] A matching circuit, which is in communication connection with the power amplifier, is used to ensure that the power amplifier and the focused ultrasound transducer achieve 50-ohm impedance matching;

[0008] A focused ultrasound transducer, which is in communication connection with the matching circuit, is used to apply the amplified output signal to the piezoelectric material to generate ultrasonic waves through vibration;

[0009] And an acoustic feedback signal collector, which is in communication connection with the central control module, is used to collect acoustic feedback signals during ultrasonic stimulation and send the acoustic feedback signals to the central control module so that the central control module can achieve feedback control.

[0010] The application also provides the use of the aforementioned heart rate regulation system in the preparation of a heart rate disorder treatment product.

[0011] The application also provides a heart rate regulation method, which comprises the following steps:

[0012] 1) focusing the focused ultrasound transducer on the target area;

[0013] 2) applying focused ultrasound to regulate the heart rate.

[0014] As described above, the heart rate regulation system based on focused ultrasound and the use thereof have the following beneficial effects: through the multi-degree-of-freedom mobile platform, the heart rate regulation system based on focused ultrasound provided by the application can noninvasively deliver ultrasonic energy to the target area of the heart to achieve the following effects: 1) the heart rate can be noninvasively and safely regulated; 2) the system is easy to operate; 3) the heart rate regulation effect is real-time; and 4) the heart rate regulation effect is significant and can increase the heart rate by 10% to 40%. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 The figure shows the schematic diagram of the heart rate regulation system based on focused ultrasound in the application.

[0016] Figure 2 The figure shows the regulation effect of the heart rate regulation system based on focused ultrasound in the application on the heart rate of a mouse.

[0017] Figure 3 The figure shows the result of the heart tissue section after being stimulated by the focused ultrasound in the application.

[0018] Figure 4 The figure shows the structural schematic diagram of the heart rate regulation system based on focused ultrasound in the application. DETAILED DESCRIPTION

[0019] The application provides a heart rate regulation system based on focused ultrasound, which comprises an ultrasonic stimulation module 1 for ultrasonic stimulation in different ultrasonic stimulation modes according to control instructions to achieve heart rate regulation; an electrocardiosignal acquisition module 3 for monitoring and storing electrocardiosignals and sending the monitored electrocardiosignal data; and a central control module 2 in communication connection with the ultrasonic stimulation module 1 and the electrocardiosignal acquisition module 3 for receiving the electrocardiosignal data sent by the electrocardiosignal acquisition module 3, calculating heart rate indexes, switching different ultrasonic stimulation modes according to the changes of the heart rate, and outputting control instructions to the ultrasonic stimulation module 1. The heart rate regulation system based on focused ultrasound is a device for regulating heart rate.

[0020] In some embodiments, the ultrasonic stimulation module 1 comprises a signal generator 11 in communication connection with the central control module 2 for generating ultrasonic stimulation waveforms according to the control instructions of the central control module 2; a power amplifier 12 in communication connection with the signal generator 11 for amplifying the output signals of the signal generator 11 to drive the focused ultrasonic transducer 14 to work; a matching circuit 13 in communication connection with the power amplifier 12 for ensuring that the power amplifier 12 and the focused ultrasonic transducer 14 achieve 50-ohm impedance matching; a focused ultrasonic transducer 14 in communication connection with the matching circuit 13 for applying the amplified output signals to piezoelectric materials to generate ultrasonic waves through vibration; and an acoustic feedback signal collector 15 in communication connection with the central control module 2 for collecting acoustic feedback signals during ultrasonic stimulation and sending the acoustic feedback signals to the central control module 2 to enable the central control module 2 to achieve feedback control.

[0021] Further, the signal generator 11 can be an arbitrary waveform generator.

[0022] Further, the acoustic feedback signal collector 15 comprises a passive cavitation detection probe 151 for receiving acoustic feedback signals and transmitting the acoustic feedback signals to a data collector; and a first data collector 152 in communication connection with the passive cavitation detection probe 151 for transmitting the acoustic feedback signals to the central control module 2; and the central control module 2 is further used for receiving the acoustic feedback signals to perform frequency domain analysis to estimate cavitation effects, calculating the curve area of a specific frequency band of a frequency spectrum for real-time feedback regulation of the energy of emitted ultrasonic waves.

[0023] In some embodiments, the ECG signal acquisition module 3 comprises an acquisition electrode 31 configured to contact the living body to acquire an ECG signal; a signal amplifier 32 communicatively connected to the acquisition electrode 31 and configured to amplify the ECG signal acquired by the acquisition electrode; and a second data collector 33 communicatively connected to the central control module 2 and configured to receive the amplified ECG signal and transmit the ECG signal to the central control module 2. The central control module 2 is further configured to obtain a heart rate from the ECG signal after receiving the ECG signal, compare the heart rate with a preset heart rate threshold, determine a current heart rate state based on the comparison, and output a signal for generating an ultrasonic stimulation waveform according to the determined heart rate state.

[0024] In some embodiments, the different ultrasonic stimulation modes correspond to different ultrasonic stimulation parameters of the focused ultrasonic transducer 14. The ultrasonic stimulation parameters include one or more of a stimulation intensity, a pulse repetition frequency, a duty cycle, an ultrasonic duration, an ultrasonic center frequency, a pulse width, and a pulse number. Specifically, the stimulation intensity can be an ultrasonic acoustic pressure.

[0025] In some embodiments, the ultrasonic acoustic pressure is 0.5-10 MPa. Specifically, the ultrasonic acoustic pressure is 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, or 9-10 MPa. Preferably, the ultrasonic acoustic pressure is 1-5 MPa.

[0026] In some embodiments, the pulse repetition frequency is 1-3000 Hz. Specifically, the pulse repetition frequency is 1-5, 5-10, 10-100, 100-300, 300-500, 500-800, 800-1000, 1000-1300, 1300-1500, 1500-1800, 1800-2000, 2000-2500, or 2500-3000 Hz. Preferably, the pulse repetition frequency is 10-2000 Hz.

[0027] In some embodiments, the duty cycle is 5-60%. Specifically, the duty cycle is 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, or 50-60%.

[0028] In some embodiments, the ultrasonic duration is 10-2400 s. Specifically, the ultrasonic duration is 10-30, 30-60, 60-120, 120-300, 300-600, 600-900, 900-1200, 1200-1500, 1500-1800, 1800-2100, or 2100-2400 s. Preferably, the ultrasonic duration is 30-1800 s.

[0029] The specific implementation process of the heart rate regulation system based on focused ultrasound provided by the present application is as follows:

[0030] The ECG signal is input to the central control module 2 after being collected by the ECG signal collection module 3. The central control module 2 analyzes and processes the ECG information, converts it into heart rate information, and stores the current heart rate. The central control module 2 compares the current heart rate with the preset heart rate and generates different output signals to the signal generator 11 according to different results. The current heart rate is lower than or close to the threshold value, respectively producing two different feedback results to cause different process controls. The central control module 2 makes different responses according to different feedback results, i.e., sets different ultrasound stimulation modes. The central control module 2 sets different ultrasound stimulation parameters according to different responses, including one or more of stimulation intensity, pulse repetition frequency, duty cycle, ultrasound duration, ultrasound center frequency, pulse width, and pulse number. The signal generator 11 receives the control instructions of the central control circuit 2 and emits different ultrasound stimulation waveform signals according to the instructions. The power amplifier 12 amplifies the energy of the waveform signal, and the signal drives the focusing ultrasound transducer 14 to work after passing through the matching circuit 13. The focal point of the focusing ultrasound transducer 14 is placed at the heart stimulation site for controlling heart rate. During ultrasound stimulation, the acoustic feedback signal collector 15 collects the acoustic feedback signal and sends it to the central control module 2. The ECG signal collection module 3 monitors the ECG in real time, and the central control module 2 calculates the heart rate and detects and stores heart rate and other index data. If the heart rate is close to the threshold value set in the central control module 2, the stimulation is stopped. If the heart rate is lower than the threshold value set in the central control module 2, the above steps are repeated for ultrasound stimulation until the current heart rate approaches the preset heart rate.

[0031] In some embodiments, the central control module 2 makes different responses according to different feedback results, i.e., sets different ultrasound stimulation modes, which can usually be as follows: when the difference between the baseline heart rate and the target heart rate is less than 20%, ultrasound stimulation parameters with a sound pressure of 2.5 MPa or less, a duty cycle of 30% or less, and a pulse repetition frequency of 100 Hz or less are recommended. When the difference between the baseline heart rate and the target heart rate is greater than 20%, ultrasound stimulation parameters with a sound pressure of 2.5 MPa or more, a duty cycle of 30% or more, and a pulse repetition frequency of 100 Hz or more are recommended.

[0032] In some embodiments, the heart rate regulation system can be used for mammals, such as rodents, even-toed ungulates, odd-toed ungulates, lagomorphs, primates, etc. The primates are, for example, monkeys, apes, or Homo sapiens.

[0033] In some embodiments, the heart arrhythmia treatment product can be selected from one or more of the following products:

[0034] 1) bradycardia treatment product:

[0035] 2) arrhythmia treatment product;

[0036] 3) sick sinus syndrome treatment product.

[0037] Wherein, the bradycardia is a heart rate lower than 60 beats per minute.

[0038] The present application also provides a method for regulating heart rate, comprising the following steps:

[0039] 1) focusing the focused ultrasound transducer on the target region;

[0040] 2) applying focused ultrasound to achieve regulation of heart rate.

[0041] In some embodiments, the parameters of the focused ultrasound in step 2) comprise one or more of the following:

[0042] A) the ultrasound acoustic pressure in the parameters is 0.5-10 MPa; specifically, the ultrasound acoustic pressure is 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9 or 9-10 MPa; preferably, the ultrasound acoustic pressure is 1-5 MPa;

[0043] B) the pulse repetition frequency in the parameters is 1-3000 Hz; specifically, the pulse repetition frequency is 1-5, 5-10, 10-100, 100-300, 300-500, 500-800, 800-1000, 1000-1300, 1300-1500, 1500-1800, 1800-2000, 2000-2500 or 2500-3000 Hz; preferably, the pulse repetition frequency is 10-2000 Hz;

[0044] C) the duty cycle in the parameters is 5-60%; specifically, the duty cycle is 5-10%, 10-20%, 20-30%, 30-40%, 40-50% or 50-60%;

[0045] D) the ultrasound duration in the parameters is 10-2400 s; specifically, the ultrasound duration is 10-30, 30-60, 60-120, 120-300, 300-600, 600-900, 900-1200, 1200-1500, 1500-1800, 1800-2100 or 2100-2400 s; preferably, the ultrasound duration is 30-1800 s.

[0046] The central control module 2 in the present application can be a mobile phone, a computer device, a tablet device, a personal digital processing device, a factory back-end processing device, etc. The central control module 2 comprises at least one processor, a memory and at least one user interface.

[0047] The memory can be a volatile memory or a non-volatile memory, or both. The non-volatile memory can be a Read Only Memory (ROM), a Programmable Read-Only Memory (PROM), which is used as an external cache. By way of example and not limitation, many forms of RAM can be used, such as Static Random Access Memory (SRAM), Synchronous Static Random Access Memory (SSRAM). The memory described in the embodiments of the present application is intended to include, but not limited to, these and any other suitable categories of memory. The memory of the present application is used to store various categories of data to support the operation of the controller. Examples of these data include: any executable programs for operating on the controller, such as an operating system and an application program; the operating system contains various system programs, such as a framework layer, a core library layer, a driver layer, etc., for implementing various basic services and processing hardware-based tasks. The application program can contain various application programs, such as a media player (MediaPlayer), a browser (Browser), etc., for implementing various application services. The implementation of the regulation method provided by the present application can be included in the application program.

[0048] The regulation method disclosed in the present application can be applied in a processor or implemented by a processor. The processor can be an integrated circuit chip with signal processing capability. In the implementation process, each step of the above method can be completed by integrated logic circuits of hardware in the processor or instructions in the form of software. The above processor can be a general processor, a Digital Signal Processor (DSP), or other programmable logic devices, discrete gates or transistor logic devices, discrete hardware components, etc. The processor can implement or execute the disclosed methods, steps and logic block diagrams in the embodiments of the present application. The general processor can be a microprocessor or any conventional processor, etc. The steps of the accessory optimization method provided in conjunction with the embodiments of the present application can be directly embodied as hardware decoding processor execution completion, or executed by a combination of hardware and software modules in the decoding processor. The software module can be located in a storage medium, which is located in the memory, and the processor reads the information in the memory to complete the steps of the above method in combination with the hardware.

[0049] The user interface can include a display, a keyboard, a mouse, a trackball, a click gun, a key, a button, a touchpad, or a touch screen, etc.

[0050] In this application, the term "duty cycle" refers to the ratio of the time a signal is high (or "on" state) to the entire cycle time within a cycle. In other words, it represents the proportion of time that the signal is in an active state (e.g., output is "1" or "high"), i.e., the ratio of ultrasonic stimulation time to the entire cycle time within a cycle.

[0051] In this application, the term "communication connection" can generally be a wireless signal or an electrical signal connection. Among them, "wireless signal" is usually a signal form of radio wave transmission information, which allows devices to communicate without physical connection, and the most common form of wireless signal includes WiFi and Bluetooth wireless communication technology.

[0052] In this application, the term "focal region" is generally the region determined by measuring the half-width of the sound pressure of focused ultrasound technology, i.e., the size and shape of the focal region. Among them, the half-width refers to the width of the sound wave intensity distribution when the focal intensity reaches half of the maximum value, which helps to accurately control the treatment area.

[0053] In this application, the term "normalized heart rate (Normalized HR)" is generally the process of normalizing heart rate relative to baseline heart rate, which can more accurately assess the impact of treatment intervention or other conditions on heart rate. The specific operation is to divide the heart rate at each measurement time point by the baseline heart rate, and the result is a unitless ratio.

[0054] In this application, the term "HE staining (H&E, Hematoxylin and Eosin staining)" is generally a basic histological staining method. Through this staining, the cell nucleus and cytoplasm and extracellular matrix can be observed, which is a basic technique for evaluating tissue structure such as cell morphology and tissue pattern.

[0055] In this application, the term "TUNEL staining (TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labeling)" is generally a method for detecting DNA breaks, often used to identify and locate apoptosis. By labeling cells with DNA ends, TUNEL staining can assess cell death rates in tissues.

[0056] The advantages and features of the present application will become apparent to one skilled in the art upon examination of the following detailed description of the preferred embodiments. It is intended that all such additional systems, methods, and / or apparatus that fall within the scope of the present application be

[0057] Before the present embodiments of the application are disclosed and described, it is to be understood that the application is not limited to the specific embodiments described herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Throughout this specification and claims, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0058] When numerical ranges are given, understand that the numerical range is intended to include every number within the range and any sub-range of the range. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the application pertains. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The materials, methods, and examples provided herein are illustrative only and, in no way, limit the scope of the application. Other embodiments of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. Various embodiments of the application will be described in detail.

[0059] All mice were anesthetized with 5% isoflurane for induction and maintained with 2% isoflurane, with an air flow of 0.9 liters per minute. The mice were placed on a heated pad with a rectal temperature probe to monitor rectal temperature and minimize the effects of temperature variation on heart rate. Rectal temperature was maintained between 34.5°C and 36.5°C. The chest of the mouse was shaved with a depilatory cream and the midpoint of the line connecting the axillary fossae was marked and located on the three-axis stage. The chest was then coated with ultrasound gel and a container of degassed water was placed to ensure that the gel was free of air bubbles. The probe used had a focal region of 0.876 mm x 0.876 mm x 4.948 mm. The focused ultrasound transducer was mounted on the three-axis stage and the focal point was moved to the marked point and extended 4 to 5 mm into the body.

[0060] As Figure 1As shown, the host is connected with the signal generator. The signal output end of the signal generator is connected with the input end of the power amplifier. The output end of the power amplifier is connected with the input end of the matching circuit. The output end of the matching circuit is connected to the focused ultrasonic transducer. The signal generator is used to generate an initial electrical signal, the power amplifier amplifies the signal, the matching circuit matches the impedance of the transducer to close to 50 ohms, and delivers the signal to the focused ultrasonic transducer.

[0061] The ultrasonic parameters are set: the ultrasonic parameters of Condition 1 are acoustic pressure: 2.5 MPa, duty cycle: 30%, pulse repetition frequency: 100 Hz, ultrasonic duration: 600 s. The ultrasonic parameters of Condition 2 are acoustic pressure: 3 MPa, duty cycle: 30%, pulse repetition frequency: 100 Hz, ultrasonic duration: 600 s. The ultrasonic parameters of Condition 3 are acoustic pressure: 1 MPa, duty cycle: 30%, pulse repetition frequency: 100 Hz, ultrasonic duration: 600 s. The ultrasonic parameters of Condition 4 are acoustic pressure: 2.5 MPa, duty cycle: 10%, pulse repetition frequency: 100 Hz, ultrasonic duration: 600 s. The ultrasonic parameters of Condition 5 are acoustic pressure: 2.5 MPa, duty cycle: 1%, pulse repetition frequency: 100 Hz, ultrasonic duration: 600 s. The ultrasonic parameters of Condition 6 are acoustic pressure: 2.5 MPa, duty cycle: 30%, pulse repetition frequency: 1000 Hz, ultrasonic duration: 600 s. The ultrasonic parameters of Condition 7 are acoustic pressure: 2.5 MPa, duty cycle: 30%, pulse repetition frequency: 100 Hz, ultrasonic duration: 60 s. The ultrasonic parameters of Condition 8 are acoustic pressure: 2.5 MPa, duty cycle: 30%, pulse repetition frequency: 100 Hz, ultrasonic duration: 1800 s. Start recording electrocardiogram, and configure ultrasonic parameters in software. A stable heart rate is observed for at least five minutes, and then ultrasonic stimulation is started. Condition 1, 2, 4, 6, 7, and 8 have good heart rate regulation effect. Condition 3 and 5 have no obvious heart rate regulation effect.

[0062] In this embodiment, adjusting the ultrasound parameters can adjust the temperature rise of the focal region. Through simulation, it is obtained that the average temperature of the focal region of Condition 1 is increased by 1.011℃ after 60 seconds of ultrasound, the average temperature of the focal region of Condition 2 is increased by 1.485℃ after 60 seconds of ultrasound, the average temperature of the focal region of Condition 3 is increased by 0.167℃ after 60 seconds of ultrasound, the average temperature of the focal region of Condition 4 is increased by 0.341℃ after 60 seconds of ultrasound, the average temperature of the focal region of Condition 5 is increased by 0.034℃ after 60 seconds of ultrasound, and the average temperature of the focal region of Condition 6 is increased by 1.0258℃ after 60 seconds of ultrasound.

[0063] In this embodiment, the ultrasonic transducer is built-in with a passive cavitation detection probe, and the received signal is collected by the data collector and transmitted to the host computer. The treatment effect can be evaluated by analyzing the acoustic feedback signal. For example, the frequency domain analysis of the acoustic feedback signal can estimate the cavitation effect, the calculation of the area under the curve of the specific frequency band of the frequency spectrum can estimate the real-time ultrasonic energy, and the energy of the emitted ultrasound is adjusted according to the feedback.

[0064] In this embodiment, the measurement of the electrocardiogram signal is measured by an electrocardiogram acquisition system, which includes a needle electrode, an amplifier and a data collector. The needle electrode has three, which are inserted into the left forelimb, the right hindlimb and the left hindlimb of the mouse. The sampling frequency is set to 2000Hz. The host computer receives and stores the collected electrocardiogram signal.

[0065] The above heart rate regulation results are as follows Figure 2As shown, the interval between the dashed lines is the interval of ultrasound application, in which the heart rate is significantly increased. The heart rate regulation effect of ultrasound stimulation is monotonously correlated with the sound pressure. Ultrasound stimulation of 1 MPa failed to increase the heart rate. However, increasing the pressure to 2.5 MPa and 3 MPa resulted in an increase in heart rate compared with the control group. Ultrasound stimulation of 3 MPa resulted in a more significant increase in heart rate (ultrasound stimulation of 2.5 MPa increased the heart rate by 16.785 ± 1.478%, and ultrasound stimulation of 3 MPa increased the heart rate by 38.135 ± 2.849%). The heart rate regulation effect is also positively correlated with the duty cycle. Ultrasound stimulation of 1% duty cycle failed to result in an increase in heart rate. Increasing the duty cycle to 10% resulted in an increase in heart rate, and a 30% duty cycle further increased the amount of heart rate increase (ultrasound stimulation of 10% duty cycle increased the heart rate by 7.654 ± 1.197%, and ultrasound stimulation of 30% duty cycle increased the heart rate by 16.785 ± 1.478%). Ultrasound stimulation of 60 seconds resulted in a linear increase in the heart rate of mice. In addition, the heart rate of mice showed a higher increase during ultrasound stimulation of 1800 seconds. Prolonging the duration of ultrasound stimulation resulted in a more significant increase in heart rate (ultrasound stimulation of 60 seconds, 600 seconds, and 1800 seconds increased the heart rate by 6.297 ± 0.255%, 16.785 ± 1.478%, and 31.928 ± 3.619%, respectively). Higher pulse repetition frequency stimulation resulted in a more significant increase in heart rate (ultrasound stimulation of 100 Hz pulse repetition frequency increased the heart rate by 16.785 ± 1.478%, and ultrasound stimulation of 1000 Hz pulse repetition frequency increased the heart rate by 25.175 ± 2.197%). Ultrasound stimulation on the legs of mice did not result in an increase in heart rate.

[0066] Example 2 Verification of the safety of the heart rate regulation system

[0067] To evaluate the safety of focused ultrasound in regulating heart rate, after the heart rate regulation experiment, the mice were subjected to heart perfusion and the heart was removed. HE staining and TUNEL staining analysis were performed on the mouse heart sections.

[0068] The main steps of HE staining are as follows: the tissue is fixed in 4% paraformaldehyde for 24 hours, subjected to a series of alcohol dehydration treatment, and treated with xylene and wax. Subsequently, paraffin embedding is used, and the sections are cut into 4 pm thick slices by a microtome. The sections are flattened in warm water and transferred to glass slides. The cell nucleus is stained with hematoxylin, differentiated with acid alcohol, treated with ammonia water for counterstaining, and then stained in eosin staining solution. The sections are dehydrated with alcohol, cleaned with xylene, and finally encapsulated with neutral resin. After drying, it is covered with a glass slide. The stained sections are observed using a microscope, and image capture and analysis are performed.

[0069] The main steps of TUNEL staining are: paraffin-embedded sections are deparaffmized in xylene for 15 minutes, dehydrated by a series of increasing concentrations of ethanol, and finally washed in distilled water. Subsequently, the sections are treated with a protease K solution at 37°C for 30 minutes, then washed with PBS. Membrane permeabilization is performed, followed by additional PBS washes. Then, the sections are incubated with the enzyme solution and the labeling solution at 37°C for 2 hours in a humidified chamber. After incubation, the sections are mounted with an antifluorescence mounting medium, and fluorescent micrographs are taken using an inverted fluorescence microscope.

[0070] The results are shown in FIG. 6. No structural damage or apoptosis of myocardial tissue in the focal region was found by histological analysis. Figure 3

[0071] The above examples are intended to illustrate the embodiments disclosed in the present application, and should not be understood as limiting the present application. In addition, various modifications listed herein and changes in the method of the present application are obvious to those skilled in the art without departing from the scope and spirit of the present application. Although the present application has been specifically described in connection with various preferred embodiments thereof, it should be understood that the present application should not be limited to these specific embodiments. In fact, various modifications as described above to those skilled in the art to obtain the present application should be included within the scope of the present application.​

Claims

1. A heart rate control system based on focused ultrasound, characterized in that, The heart rate control system includes: The ultrasound stimulation module (1) is used to perform ultrasound stimulation in different ultrasound stimulation modes according to control commands to achieve heart rate regulation. The electrocardiogram (ECG) signal acquisition module (3) is used to monitor and store ECG signals and send the monitored ECG data; the central control module (2) is communicatively connected to both the ultrasound stimulation module (1) and the ECG signal acquisition module (3), and is used to receive the ECG data sent by the ECG signal acquisition module (3), calculate the heart rate index, and switch different ultrasound stimulation modes according to the changes in heart rate, and output control commands to the ultrasound stimulation module (1).

2. The heart rate regulation system according to claim 1, characterized in that, The ultrasound stimulation module (1) includes: The signal generator (11) is connected in communication with the central control module (2) and is used to receive control commands from the central control module (2) to generate ultrasonic stimulation waveforms. The power amplifier (12) is communicatively connected to the signal generator (11) and is used to amplify the output signal of the signal generator (11) to drive the focused ultrasound transducer (14) to work. Matching circuit (13), which is communicatively connected to the power amplifier (12), is used to ensure that the power amplifier (12) and the focused ultrasound transducer (14) achieve an impedance matching of 50 ohms; A focused ultrasonic transducer (14) is communicatively connected to the matching circuit (13) and is used to apply the amplified output signal to the piezoelectric material to generate ultrasonic waves by causing it to vibrate. The acoustic feedback signal acquisition unit (15) is communicatively connected to the central control module (2) and is used to acquire acoustic feedback signals during ultrasonic stimulation and send acoustic feedback signals to the central control module (2) so that the central control module (2) can realize feedback control.

3. The heart rate regulation system according to claim 2, characterized in that, The acoustic feedback signal acquisition unit (15) includes: a passive cavitation detection probe (151) for receiving acoustic feedback signals and transmitting the acoustic feedback signals to a data acquisition unit; and a first data acquisition unit (152) for communicating with the passive cavitation detection probe (151) and transmitting the acoustic feedback signals to the central control module (2). The central control module (2) is also used to receive acoustic feedback signals, perform frequency domain analysis to estimate cavitation effects, calculate the area under the curve of a specific frequency band of the spectrum, and adjust the energy of the emitted ultrasound in real time.

4. The heart rate regulation system according to claim 1, characterized in that, The electrocardiogram signal acquisition module (3) includes: acquisition electrodes (31) for contacting a living organism to acquire electrocardiogram signals; A signal amplifier (32) is communicatively connected to the acquisition electrode (31) and is used to amplify the electrocardiogram signal obtained by the acquisition electrode; a second data acquisition unit (33) is communicatively connected to the central control module (2) and is used to receive the amplified electrocardiogram signal and transmit the electrocardiogram signal to the central control module (2). The central control module (2) is also used to receive the electrocardiogram signal, obtain the heart rate based on the electrocardiogram signal, compare the heart rate with the preset heart rate threshold, determine the current heart rate state, and output a signal for generating an ultrasound stimulation waveform based on the determined heart rate state.

5. The heart rate regulation system according to claim 2, characterized in that, Different ultrasound stimulation modes correspond to different ultrasound stimulation parameters of the focused ultrasound transducer (14); the ultrasound stimulation parameters include one or more of stimulation intensity, pulse repetition frequency, duty cycle, ultrasound duration, ultrasound center frequency, pulse width, and number of pulses; preferably, the stimulation intensity is ultrasound sound pressure.

6. The heart rate regulation system according to claim 5, characterized in that, The ultrasound stimulation parameters include one or more of the following characteristics: 1) The ultrasonic sound pressure level is 0.5-10 MPa; 2) The pulse repetition frequency is 1-3000Hz; 3) The duty cycle is 5-60%; 4) The duration of the ultrasound is 10-2400s.

7. Use of the heart rate regulation system according to any one of claims 1-6 in the preparation of a heart rate arrhythmia treatment products.

8. The use according to claim 7, characterized in that, The arrhythmia treatment product may be selected from one or more of the following products: 1) Bradycardia treatment products: 2) Products for treating arrhythmia; 3) Products for the treatment of bradycardia-tachycardia syndrome.

Images