A vagus nerve stimulation device and stimulation parameter optimization method

Abstract

This invention provides a vagus nerve stimulation device and a stimulation parameter optimization method. The device includes a programmer and a pulse generator. The pulse generator is wirelessly connected to the programmer and is used to convert programming commands sent by the programmer into a rapid pacing pulse sequence or a vagus nerve stimulation pulse sequence. The pulse generator is connected to a vagus nerve stimulation electrode, a right ventricular photoplethysmography (PVP) composite electrode, and a right ventricular pacing electrode via electrode interfaces. The vagus nerve stimulation electrode generates a first electrical stimulation based on the vagus nerve stimulation pulse sequence. The right ventricular PVP composite electrode acquires PVP data at a set location. The right ventricular pacing electrode generates a second electrical stimulation based on the rapid pacing pulse sequence and acquires intracardiac electrocardiogram (ICG) data during the first electrical stimulation. The pulse generator obtains cardiovascular physiological parameter data based on the PVP data and heart rate detection data based on the ICG data, and transmits the data wirelessly to the programmer.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biomedical engineering, in particular to a vagus nerve stimulation device and a stimulation parameter optimization method. BACKGROUND

[0002] Heart failure, also known as heart failure, is a serious and terminal stage of various heart diseases, and is one of the most important cardiovascular diseases. There are about 4.5 million heart failure patients in China, and the number is increasing rapidly with the aging of the population.

[0003] The function of cardiac autonomic nerve mainly manifests as chronotropy, inotropy, conduction and threshold. Autonomic nerve dysfunction is a known cardiovascular risk indicator, and imbalance between parasympathetic and sympathetic nervous systems is a recognized factor in the progression of heart failure. Overexcitation of the sympathetic nervous system plays a major role in the main pathogenesis of heart failure, and blocking this key process is the basis for effective treatment of heart failure. Vagus nerve stimulation can inhibit the overexcitation of the sympathetic nervous system, restore parasympathetic activity, increase vagal tone and reflex, and functionally block the overexcitation of the sympathetic nervous system to reestablish the balance of autonomic nervous system function and reverse the progression of heart failure.

[0004] However, the regulation mechanism of cardiac autonomic nerve is very complex, and the mechanism of vagus nerve stimulation is still not fully understood. Many factors that adjust the function of cardiac autonomic nerve are often affected by parasympathetic and sympathetic nervous systems, and the influence and time of action are different in different stages and individuals. Therefore, it is of great significance to obtain the evaluation of the influence of different stimulation modes and stimulation parameters on cardiovascular response through animal experiments, and then obtain the optimal combination of stimulation modes and stimulation parameters.

[0005] However, the existing vagus nerve stimulation device has a single function, only has a program-controlled pulse stimulation function, and cannot directly obtain the evaluation of the influence of different stimulation modes and stimulation parameters on cardiovascular response. When using the existing vagus nerve stimulation device for related animal experiments, a large number of external devices are needed to measure the surface electrocardiogram of the animal, various related hemodynamic parameters, etc. The measurement process mainly relies on manual operation by the experimenters, which is not only complicated and time-consuming, but also prone to errors, which is difficult to find and correct, and brings great risks to subsequent data analysis and processing. At the same time, the existing stimulation parameter optimization method of ergodicity optimization in the experiment only selects 3 stimulation parameters with 256 quantization levels for combination, and only tests each combination for 10 minutes, so the total time of ergodicity optimization is more than 310 years, making it difficult to obtain the optimal combination of stimulation modes and stimulation parameters. SUMMARY

[0006] In view of the problems in the prior art, the vagus nerve stimulation device and the stimulation parameter optimization method are provided, which are reasonable in design, simple in structure, complete in function, high in success rate of experiment, high in optimization efficiency and low in experimental cost.

[0007] The present application is realized by the following technical solutions:

[0008] The present application provides a vagus nerve stimulation device, comprising a program control instrument and a pulse generator;

[0009] The pulse generator is connected with the program control instrument through wireless interaction, and is used for converting the program control instruction sent by the program control instrument into a fast pacing pulse sequence or a vagus nerve stimulation pulse sequence;

[0010] The pulse generator is connected with the vagus nerve stimulation electrode, the right ventricular photoelectric plethysmogram composite electrode and the right ventricular pacing electrode through the electrode interface respectively;

[0011] The vagus nerve stimulation electrode is used for generating a first electric stimulation according to the vagus nerve stimulation pulse sequence;

[0012] The right ventricular photoelectric plethysmogram composite electrode is used for acquiring photoelectric plethysmogram data at a set position;

[0013] The right ventricular pacing electrode is used for generating a second electric stimulation according to the fast pacing pulse sequence, and collecting intracavity electrocardiogram data during the first electric stimulation;

[0014] The pulse generator is used for obtaining cardiovascular physiological parameter data according to the photoelectric plethysmogram data, obtaining heart rate detection data according to the intracavity electrocardiogram data, and sending the data to the program control instrument through wireless transmission.

[0015] Optionally, the pulse generator comprises a power supply and a microcontroller, and a Bluetooth module and an antenna, a right ventricular apex fast pacing module, a right ventricular blood flow monitoring module and a vagus nerve stimulation module which are connected with the microcontroller through interaction respectively;

[0016] The microcontroller is used for converting the program control instruction sent by the program control instrument into corresponding driving pulse parameters;

[0017] The right ventricular apex fast pacing module is used for converting the program control instruction sent by the program control instrument into a fast pacing pulse sequence, and detecting heart rate detection data according to the intracavity electrocardiogram data;

[0018] The right ventricular blood flow monitoring module obtains cardiovascular physiological parameter data according to the photoelectric plethysmogram data;

[0019] The vagus nerve stimulation module is used for converting the program control instruction sent by the program control instrument into a vagus nerve stimulation pulse sequence.

[0020] Optionally, the right ventricular apex rapid pacing module comprises a pacing pulse generation unit, a pacing pulse emission unit, a heart rate detection unit and an intracardiac electrocardio sensing unit;

[0021] The pacing pulse generation unit is configured to generate a corresponding pacing stimulation pulse control signal according to the drive pulse parameters of the microcontroller;

[0022] The pacing pulse emission unit is configured to generate a rapid pacing pulse sequence according to the pacing stimulation pulse control signal and output it;

[0023] The heart rate detection unit is configured to receive the intracardiac electrocardiogram data collected by the right ventricular pacing electrode and transmit it to the intracardiac electrocardio sensing unit;

[0024] The intracardiac electrocardio sensing unit is configured to detect heart rate detection data according to the intracardiac electrocardiogram data and output it to the microcontroller.

[0025] Optionally, the right ventricular blood flow monitoring module comprises a drive pulse generation unit, a red light driving unit, an infrared driving unit, a photoplethysmogram detection unit and a physiological parameter detection unit;

[0026] The drive pulse generation unit is configured to generate a corresponding drive pulse control signal according to the drive pulse parameters sent by the microcontroller and transmit it to the red light driving unit and the infrared driving unit.

[0027] The red light driving unit is configured to generate a red light driving signal according to the received drive pulse control signal, and the red light driving signal is delivered to the photoplethysmogram composite electrode through the electrode interface to drive the red light emitting diode therein to emit light;

[0028] The infrared driving unit is configured to generate an infrared driving signal according to the received drive pulse control signal, and the infrared driving signal is delivered to the photoplethysmogram composite electrode through the electrode interface to drive the infrared light emitting diode therein to emit light;

[0029] The photoplethysmogram detection unit is connected to the photoplethysmogram composite electrode through the electrode interface, receives the red light and infrared light intensity signals detected by the photodiode therein to obtain photoplethysmogram data, and sends it to the physiological parameter detection unit;

[0030] The physiological parameter detection unit detects cardiovascular physiological parameter data according to the received photoplethysmogram data and sends it to the microcontroller.

[0031] Optionally, the vagus nerve stimulation module comprises a vagus nerve stimulation pulse generation unit and a vagus nerve stimulation pulse emission circuit connected in sequence,

[0032] The vagus nerve stimulation pulse generation unit is used to convert the program control instruction sent by the program controller into a stimulation pulse control signal;

[0033] The vagus nerve stimulation pulse generation circuit is used to generate a vagus nerve stimulation pulse sequence according to the stimulation pulse control signal and deliver the stimulation pulse to the vagus nerve stimulation electrode through the electrode interface.

[0034] The present application also provides a vagus nerve stimulation parameter optimization method, comprising,

[0035] Obtaining the cardiovascular function parameters of the experimental animal in a resting state, and calculating a function function reference value through a preset cardiovascular function function;

[0036] Randomly selecting a vagus nerve stimulation parameter combination according to the distribution of each vagus nerve stimulation parameter as the set vagus nerve stimulation initial parameter;

[0037] Obtaining the intracavity electrocardiogram data and the photoplethysmogram data during the stimulation according to the vagus nerve stimulation initial parameter after the exercise of the experimental animal, and calculating a function function actual value through a preset cardiovascular function function;

[0038] Calculating the deviation between the function function actual value and the function function reference value, and mathematically optimizing the deviation to obtain an optimal vagus nerve stimulation parameter combination.

[0039] Optionally, the preset cardiovascular function function is as follows,

[0040]

[0041] Wherein, HF(t) is the cardiovascular function function value at t time; HR(t) is the heart rate at t time; HR Ref is the heart rate reference value at normal rest; RESP(t) is the respiratory rate at t time; RESP Ref is the respiratory rate reference value at normal rest; HRV(t) is the heart rate variability at t time; HRV Ref is the heart rate variability reference value at normal rest; SvO2(t) is the mixed venous oxygen saturation at t time; is the mixed venous oxygen saturation reference value at normal rest; is the maximum rise rate of intraventricular pressure within the heart beat at t time; is the maximum rise rate of intraventricular pressure reference value at normal rest; K1-K5 are proportional factors of each item.

[0042] Optionally, the one vagus nerve stimulation parameter combination at least includes five of the current amplitude, the voltage amplitude, the pulse width, the pulse delay, the pulse duration, the output pulse number and the pulse interval.

[0043] Optionally, the mathematical optimization adopts a simplex down method or a modified simplex down method, and a stimulation parameter combination corresponding to a minimum value of the deviation is an optimal stimulation parameter combination.

[0044] Optionally, the calculation of the deviation between the actual value of the function function and the reference value of the function function, the mathematical optimization of the deviation, and the obtaining of the optimal vagus nerve stimulation parameter combination further include the following steps,

[0045] If the actual value of the function function corresponding to the initial vagus nerve stimulation parameter does not reach the optimization requirement, a new set of vagus nerve stimulation parameters is randomly generated, the corresponding actual value of the function function is calculated, and the mathematical optimization is performed again until the optimal vagus nerve stimulation parameter combination is obtained.

[0046] Compared with the prior art, the vagus nerve stimulation device has the following beneficial technical effects:

[0047] In the vagus nerve stimulation device, the program-controlled instrument sends program-controlled stimulation parameters to the pulse generator through a wireless mode, generates a program-controlled right ventricular rapid pacing pulse sequence and a vagus nerve stimulation pulse sequence respectively, delivers the sequences to a right ventricular rapid pacing electrode and a vagus nerve stimulation electrode through an electrode interface, generates corresponding electrical stimulation, and drives a right ventricular photoelectric plethysmography composite electrode to collect intracardiac electrocardiogram data and right ventricular photoelectric plethysmography data in the right ventricular cavity. The collected intracardiac electrocardiogram data and right ventricular photoelectric plethysmography data are uploaded to the external program-controlled instrument for analysis in a wireless Bluetooth mode. Not only the program-controlled stimulation of the vagus nerve is realized, but also the stimulation parameter optimization of the vagus nerve stimulation is realized by the stimulation parameter optimization method deployed in the external program-controlled instrument, so that the optimal stimulation parameters are obtained, and the response rate of the vagus nerve stimulation is improved.

[0048] In the vagus nerve stimulation parameter optimization method, a cardiovascular function function is constructed by using cardiovascular function parameters of a heart failure animal subjected to stimulation parameter selection optimization, the cardiovascular function parameters of the heart failure animal in a resting state before modeling are used as reference values, any vagus nerve stimulation parameter combination is randomly selected for vagus nerve stimulation, cardiovascular function parameters under the vagus nerve stimulation condition including heart rate recovery are recorded, the cardiovascular function function value and the difference between the cardiovascular function function value and the reference value are calculated, and the vagus nerve stimulation is performed again by changing the vagus nerve stimulation parameter combination multiple times. The optimal stimulation parameter corresponds to the minimum difference between the cardiovascular function function value and the reference value in the selected stimulation parameter. Meanwhile, a mathematical optimization method is adopted, and specifically, a simplex down method or a modified method thereof is used. Only a small amount of experimental iteration calculation is required for the optimization of the stimulation parameter, so that the stimulation parameter combination closest to the cardiovascular function function reference value is obtained, and a vagus nerve stimulation parameter optimization method combining a mathematical optimization method and an animal exercise experiment is realized. BRIEF DESCRIPTION OF DRAWINGS

[0049] Figure 1 The schematic diagram of the vagus nerve stimulation device structure in the embodiment of the present application.

[0050] Figure 2 The schematic diagram of the pulse generator structure in the embodiment of the present application.

[0051] Figure 3 The schematic diagram of the power supply structure in the embodiment of the present application.

[0052] Figure 4 The schematic diagram of the right ventricular apex rapid pacing module workflow in the embodiment of the present application.

[0053] Figure 5 The schematic diagram of the right ventricular blood flow monitoring module workflow in the embodiment of the present application.

[0054] Figure 6 The schematic diagram of the vagus nerve stimulation module workflow in the embodiment of the present application.

[0055] Figure 7 The schematic diagram of the pulse generator stimulation pulse output parameters in the embodiment of the present application.

[0056] Figure 8 The measured diagram of the output pulse of the right ventricular apex rapid pacing module in the embodiment of the present application.

[0057] Figure 9 The measured diagram of the output pulse of the vagus nerve stimulation module in the embodiment of the present application.

[0058] Figure 10 The schematic diagram of the vagus nerve stimulation parameter optimization method steps in the embodiment of the present application. DETAILED DESCRIPTION

[0059] The present application will be further described in detail below in combination with specific embodiments, which are an explanation rather than a limitation of the present application.

[0060] The present application aims at the problem that the existing vagus nerve stimulation device has a single function, only has a program-controlled pulse stimulation firing function, cannot directly obtain the evaluation of the influence of different stimulation modes and stimulation parameters on cardiovascular response, the measurement process mainly relies on manual operation of experimenters, is not only complicated and time-consuming in operation, but also is very easy to cause mistakes, and it is more difficult to find and correct the mistakes, and the stimulation parameter optimization method is a time-consuming and difficult task, and proposes a vagus nerve stimulation device and a stimulation parameter optimization method.

[0061] The vagus nerve stimulation device of the present application, as shown in Figure 1 includes the following components:

[0062] Programmed instrument 1, placed outside the experimental animal, generates and sends a series of programmed instructions with adjustable stimulation parameters such as pulse amplitude, pulse width, pulse period, etc. according to the stimulation parameter optimization method, receives the intracavity electrocardiogram and photoplethysmogram and other physiological signals uploaded by the pulse generator 2, and optimizes the stimulation parameters according to the current value of the cardiovascular function function. The programmed instrument 1 can be a computer, a tablet computer or a smart phone and other data terminals. The instructions generated by the programmed instrument 1 are transmitted to the pulse generator 2 by wireless Bluetooth, and the photoplethysmogram data and intracavity electrocardiogram data detected by the pulse generator 2 from the right ventricular cavity of the experimental animal are uploaded to the programmed instrument 1 for analysis by wireless Bluetooth.

[0063] The pulse generator 2 receives the programmed instructions sent by the programmed instrument 1 by wireless Bluetooth, generates a programmed fast pacing pulse sequence or a vagus nerve stimulation pulse sequence, and delivers it to the right ventricular pacing electrode 5, the vagus nerve stimulation electrode 3 and the right ventricular photoplethysmogram composite electrode 4 through the electrode interface 27 respectively, and drives the right ventricular photoplethysmogram composite electrode 4. At the same time, it collects the intracavity electrocardiogram data and the photoplethysmogram data in the right ventricular cavity, and uploads the detected intracavity electrocardiogram data and photoplethysmogram data in the right ventricular cavity to the programmed instrument 1 for analysis by wireless Bluetooth. In the experiment or use, the pulse generator 2 needs to be implanted in the experimental animal.

[0064] The vagus nerve stimulation electrode 3 delivers the vagus nerve stimulation pulse sequence generated by the pulse generator 2 to the right carotid vagus nerve bundle of the experimental animal to produce a stimulation effect. In the experiment or use, the vagus nerve stimulation electrode 3 is implanted in the right neck of the experimental animal. The proximal end is connected to the electrode interface 27 of the pulse generator 2, and the distal end is connected to the right carotid vagus nerve bundle.

[0065] The photoplethysmogram composite electrode 4 is used to obtain the right ventricular hemodynamic parameters of the experimental animal to evaluate the effect of vagus nerve stimulation on cardiovascular function. In the experiment or use, it is implanted in the right ventricle of the experimental animal.

[0066] The right ventricular pacing electrode 5 detects the intracavity electrocardiogram during vagus nerve stimulation to obtain the evaluation of the effect of vagus nerve stimulation on cardiovascular function. In the experiment or use, it is implanted in the right ventricle of the experimental animal, and is used to pace the experimental animal to establish a heart failure model.

[0067] In particular, in the programmed instrument 1, the stimulation parameter optimization method is deployed to optimize the stimulation parameters of vagus nerve stimulation, and then the optimal stimulation parameters with the best treatment effect on heart failure are obtained, and the response rate of vagus nerve stimulation is improved.

[0068] In particular, as Figure 2As shown, the pulse generator 2 comprises a power supply 21, a microcontroller 22, a Bluetooth module and antenna 23, a right ventricular apex rapid pacing module 24, a right ventricular blood flow monitoring module 25, a vagus nerve stimulation module 26, and an electrode interface 27. Among them:

[0069] The power supply 21 is used to provide power supply for each part of the pulse generator 2. As shown, it comprises a battery 211, a reed switch circuit 212, and a voltage stabilizing circuit 213. Figure 3

[0070] The battery 211 is preferably an implantable primary battery of the series produced by Greatbatch Medical Company.

[0071] The reed switch circuit 212 can be opened or closed under the action of an external magnet to turn on or off the battery output.

[0072] The voltage stabilizing circuit 213 stabilizes the power supply voltage provided by the battery at a specified voltage for use by the circuits in the pulse generator.

[0073] The microcontroller 22, also known as MCU, is responsible for controlling and coordinating the operation of each circuit in the pulse generator. It is preferably a single-chip microcomputer of the MSP430 series produced by Texas Instruments Company.

[0074] The Bluetooth module and antenna 23 are responsible for completing the bidirectional data communication between the pulse generator 2 and the external programmer 1.

[0075] The right ventricular apex rapid pacing module 24. As shown, it comprises a pacing pulse generation unit 241, a pacing pulse delivery unit 242, a heart rate detection unit 243, and an intracardiac electrocardio sensing unit 244. Among them: Figure 4 The pacing pulse generation unit 241 receives pacing stimulation parameters from the microcontroller 22, generates corresponding pacing stimulation pulse control signals according to the programmed parameters, and transmits them to the pacing pulse delivery unit 242.

[0076] The pacing pulse delivery unit 242 receives the stimulation pulse control signals transmitted from the pacing pulse generation unit 241, generates pacing stimulation pulses through internal circuits, and delivers the stimulation pulses to the right ventricular pacing electrode 5 through the electrode interface 27. The waveform parameters of a typical pacing pulse are as shown in

[0077] Figure 7 The oscilloscope screenshot of the pacing pulse output is as shown in Figure 8

[0078] The intracardiac electrocardio sensing unit 244 is connected to the right ventricular pacing electrode 5 through the electrode interface 27, senses the intracardiac electrocardiogram in the right ventricular cavity, and sends it to the heart rate detection unit 243.

[0079] ​​​The heart rate detection unit 243 receives the intracavity electrocardiogram from the intracavity electrocardiogram sensing unit 244, and detects the heart rate, heart rate variability and other cardiovascular parameters, and sends them to the microcontroller 22.

[0080] The right ventricular blood flow monitoring module 25, as shown in Figure 5 includes a drive pulse generation unit 251, a red light drive unit 252, an infrared drive unit 253, a photoplethysmogram detection unit 255, and a physiological parameter detection unit 254, wherein:

[0081] The drive pulse generation unit 251 receives the drive pulse parameters from the microcontroller 22, generates corresponding drive pulse control signals according to the drive pulse parameters, and sends them to the red light drive unit 252 and the infrared drive unit 253.

[0082] The red light drive unit 252 receives the drive pulse control signals sent by the drive pulse generation unit 251, generates red light drive signals through internal circuits, and delivers the drive pulse signals to the photoplethysmogram composite electrode 4 through the electrode interface 27 to drive the red light emitting diode therein to emit light.

[0083] The infrared drive unit 253 receives the drive pulse control signals sent by the drive pulse generation unit 251, generates infrared drive signals through internal circuits, and delivers the drive pulse signals to the photoplethysmogram composite electrode 4 through the electrode interface 27 to drive the infrared light emitting diode therein to emit light.

[0084] The photoplethysmogram detection unit 255 is connected to the photoplethysmogram composite electrode 4 through the electrode interface 27, receives the red light and infrared light intensity signals detected by the photodiode therein, and sends them to the physiological parameter detection unit 254.

[0085] The physiological parameter detection unit 254 receives the photoplethysmogram data from the photoplethysmogram detection unit 255, detects the heart rate, blood oxygen saturation, heart rate variability and other cardiovascular physiological parameters, and sends them to the microcontroller 22.

[0086] The vagus nerve stimulation module 26, as shown in Figure 6 includes a vagus nerve stimulation pulse generation unit 261 and a vagus nerve stimulation pulse emission circuit 262. Wherein:

[0087] The vagus nerve stimulation pulse generation unit 261 receives the vagus nerve stimulation parameters from the microcontroller 22, generates corresponding vagus nerve stimulation pulse control signals according to the vagus nerve stimulation parameters, and sends them to the vagus nerve stimulation pulse emission circuit 262.

[0088] The vagus nerve stimulation pulse generation circuit 262 receives the stimulation pulse control signal from the vagus nerve stimulation pulse generation unit 261, generates a vagus nerve stimulation pulse sequence through internal circuitry, and delivers the stimulation pulse to the vagus nerve stimulation electrode 3 through the electrode interface 27. The waveform parameters of a typical vagus nerve stimulation pulse are as shown in Table 1. Figure 7 The oscilloscope screenshot of the vagus nerve stimulation pulse output is as shown in Table 2. Figure 9

[0089] The electrode interface 27 includes four IS-1 standard small-section connector electrode interfaces, which respectively realize the physical and electrical connection of the right ventricular apex rapid pacing module 24, the right ventricular blood flow monitoring module 25, the vagus nerve stimulation module 26, and the right ventricular pacing electrode 5, the photoplethysmography composite electrode 4, and the vagus nerve stimulation electrode 5. Among them, one IS-1 connector realizes the electrical connection of the right ventricular apex rapid pacing module 24 and the right ventricular pacing electrode 5; one IS-1 connector realizes the electrical connection of the vagus nerve stimulation module 26 and the vagus nerve stimulation electrode 3; and two IS-1 connectors are combined to realize the electrical connection of the right ventricular blood flow monitoring module 25 and the photoplethysmography composite electrode 4.

[0090] Correspondingly, the vagus nerve stimulation parameter optimization method of the present application includes the following steps as shown in Table 3. Figure 10

[0091] Step 1: Construct a cardiovascular function function. Record the cardiovascular function parameters of the experimental animal after exercise, such as heart rate, respiratory rate, heart rate variability, mixed venous oxygen saturation, dP / dt, etc., to construct a cardiovascular function function with cardiovascular function parameters. As shown in formula (1).

[0092]

[0093] Among them, HF is the cardiovascular function function, HF(t) is the cardiovascular function function value at time t; HR(t) is the heart rate at time t, with the unit of BPM, HR Ref is the heart rate reference value at normal rest, obtained by actual test of the experiment; RESP(t) is the respiratory rate at time t, with the unit of BPM, RESP Ref is the respiratory rate reference value at normal rest, obtained by actual test of the experiment; HRV(t) is the heart rate variability at time t, preferably SD2 / SD1, which is a dimensionless value, HRV Ref is the heart rate variability reference value at normal rest, obtained by actual test of the experiment; SvO2(t) is the mixed venous oxygen saturation at time t, which is a percentage, is the mixed venous oxygen saturation reference value at normal rest, obtained by actual test of the experiment; ​​is the maximum rise rate of intraventricular pressure in the heart beat at time t, with unit of mmHg / S, is the reference value of the maximum rise rate of intraventricular pressure at normal resting state, which is obtained by actual test; K1-K5 are proportional factors of each item, which are real numbers and obtained by actual test. t is the instantaneous time, which is a real number greater than zero.

[0094] Step 2, obtaining the reference value of the function. Record the cardiovascular function parameters of the experimental animal in resting state, and calculate the cardiovascular function as the reference value.

[0095] Step 3, setting the initial parameters of vagus nerve stimulation. Randomly select a vagus nerve stimulation parameter combination (at least including 5 items of current amplitude, voltage amplitude, pulse width, pulse delay, pulse duration, output pulse number, and pulse interval) according to the distribution of each stimulation parameter, and prepare to perform vagus nerve stimulation.

[0096] Step 4, performing vagus nerve stimulation. In the preferred example, the experimental animal is immediately stimulated for 5 minutes after exercise, and the intracavity electrocardiogram and photoplethysmogram data reflecting the hemodynamic parameters during the stimulation are recorded through the right ventricular pacing electrode and the right ventricular photoplethysmogram composite electrode respectively, and uploaded to the programmed instrument 1 outside the body in a wireless Bluetooth manner.

[0097] Step 5, calculating the actual value of the function. The current actual value of the cardiovascular function is calculated according to the measured intracavity electrocardiogram and hemodynamic parameters.

[0098] Step 6, calculating the deviation of the function from the reference value. The deviation between the current actual value of the cardiovascular function and the reference value is calculated.

[0099] Step 7, performing NM optimization and judging whether the optimal value is found. The deviation between the current actual value of the cardiovascular function and the reference value is calculated and mathematically optimized to find the optimal vagus nerve stimulation parameter combination by using the simplex down method or its improved method. The stimulation parameter combination corresponding to the minimum value of the difference between the cardiovascular function value and the reference value is the optimal stimulation parameter combination. If the optimal value is found, proceed to step 9, otherwise proceed to step 8. In the preferred example, the simplex down method or its improved method is used, including but not limited to Nelder-Mead method, NMSA simplex down-annealing hybrid algorithm, and NMGA simplex down-genetic hybrid algorithm.

[0100] Step 8, generating new stimulation parameters. If the optimal value is not found, a new set of vagus nerve stimulation parameters is randomly generated, and step 4 is repeated until the optimal stimulation parameter combination is obtained in step 7.

[0101] Step 9, output the optimal stimulation parameter combination. The optimal stimulation parameter combination content is uploaded to the external programmer through wireless Bluetooth.

[0102] When the device of the present application is used or implemented, it needs to be implanted into an experimental animal. A standard right ventricular pacing electrode 5 and a photoplethysmogram composite electrode 4 are inserted into the right ventricular apex from the right jugular vein of the experimental animal by minimally invasive intervention surgery, the vagus nerve stimulation electrode 3 is wrapped around the right vagus nerve of the experimental animal, the encapsulated pulse generator 2 is implanted in the right neck subcutaneous pocket, the electrodes are connected to the pulse generator 2, and after testing that each module is working normally, the right ventricular rapid pacing module is turned off and the vagus nerve stimulation module is turned off.

[0103] After the experimental animal is implanted with the stimulation device, anti-inflammatory treatment is performed, and after the wound heals for two weeks, the cardiovascular function parameters of the experimental animal in a resting state are recorded.

[0104] The corresponding heart failure animal model of the method of the present application is established as follows. The fast pacing module of the experimental animal whose functional function reference value has been obtained is opened to perform right ventricular apex rapid pacing. After one week of rapid right ventricular pacing, the experimental animal shows a decrease in cardiac function in terms of hemodynamics, and the degree of heart failure is further aggravated in the third and fourth weeks of pacing, the plasma endothelin increases, and symptoms such as decreased activity, decreased appetite, and shortness of breath occur, and the peritoneal cavity fluid and increased heart weight appear in pathology, which are consistent with the characteristics of congestive heart failure. In this specific example, the rapid pacing frequency for making a heart failure model is generally set to 240-260 times / minute.

[0105] Determine whether the modeling is successful. The success of the establishment of the heart failure animal model is confirmed by echocardiography. If successful, proceed to the next step, if not, return to step 1 and select a new experimental animal to reestablish the cardiovascular function function and establish the corresponding heart failure animal model.

[0106] The experimental animal after exercise described in step 4, wherein the exercise level is set according to the following. According to the first three exercise loads of the modified BRUCE exercise program, three exercise levels of high, medium and low are obtained by setting the speed and slope of the treadmill, and one of the exercise levels is selected to make the experimental animal move passively for 3 minutes to obtain the corresponding exercise load. In this specific example, the speed and slope of the first three exercise levels of the modified BRUCE exercise program are 2.74 Km / h, 10°, 4.02 Km / h, 12° and 5.47 Km / h, 14°, respectively.

[0107] In step 8, new stimulation parameters are generated. If the optimal value is not found, a new set of vagus nerve stimulation parameters is randomly generated, and after the experimental animal rests for 5-10 minutes to recover to a resting state, the exercise level is set again through the above process.

[0108] In the vagus nerve stimulation device, the conventional vagus nerve stimulation device is only limited to program-controlled pulse stimulation, and the vagus nerve stimulation treatment, heart failure animal modeling and cardiovascular function detection are integrated together, which are independent of each other, to become a complete vagus nerve stimulation device for heart failure treatment animal experiment. The device not only simplifies the surgical implantation process of the instrument, reduces the adverse effects of repeated operations on experimental animals, but also improves the experimental success rate and reduces the experimental cost. Meanwhile, the conventional program-controlled instrument program-controlled instruction sending function and the in-vivo biological information measurement function are combined to realize the dynamic combination of the program-controlled instruction sending function and the in-vivo biological information measurement function, so that the full-automatic experimental process without manual intervention is realized, the stimulation parameters are automatically set by the optimization algorithm, the cardiovascular function is automatically measured, and the optimal parameters are automatically selected. The experimental efficiency and accuracy are greatly improved, the experimental difficulty is reduced, and the traditional manual experience selection of optimal parameters is improved.

[0109] Meanwhile, the right ventricular photoelectric plethysmogram module for acquiring heart variability information dynamically senses and acquires the cardiovascular function function value corresponding to the current vagus nerve stimulation parameter, and calculates the difference between the cardiovascular function parameter reference value before heart failure modeling and the resting state, so that the influence of numerous cardiovascular function parameters on the overall cardiovascular function is comprehensively and integrally considered, and a unified function function form is established, so that the complex cardiovascular function evaluation can be converted into an easy-to-implement function function engineering calculation evaluation method.

[0110] The next set of stimulation parameter combinations is automatically generated by the optimization algorithm, transmitted to the vagus nerve stimulation module through the wireless Bluetooth mode, and stimulated by the next set of stimulation parameters. The simplex down method is repeatedly iterated and optimized, and finally the global optimal stimulation parameter combination is obtained. Therefore, the full-automatic experimental process without manual intervention is realized, the stimulation parameters are automatically set by the optimization algorithm, the cardiovascular function is automatically measured, and the optimal parameters are automatically selected. The experimental efficiency and accuracy are greatly improved, the experimental difficulty is reduced, and the traditional manual experience selection of optimal parameters is improved.

[0111] Therefore, the vagus nerve stimulation technique needs a vagus nerve stimulation device that can obtain the influence of different stimulation modes and stimulation parameters on cardiovascular response and a corresponding stimulation parameter optimization method that can quickly optimize the stimulation parameters to promote the progress of the experiment.

[0112] In the aspect of vagus nerve stimulation parameter optimization method, firstly, the cardiovascular function function is constructed, the right ventricular photoelectric plethysmography module for obtaining the heart variable information is dynamically perceived, the cardiovascular function function value corresponding to the current vagus nerve stimulation parameter is obtained, and the difference between the cardiovascular function parameter reference value before heart failure modeling and the resting state is calculated. Not only the influence of numerous cardiovascular function parameters on the overall cardiovascular function is considered comprehensively and integrally, but also a unified function function form is established, so as to convert the complex cardiovascular function evaluation into the function function engineering calculation evaluation method which is easy to realize. Secondly, the ergodic optimization method used in the conventional animal experiment is broken through, the animal experiment is combined with the mathematical optimization method, the next group of stimulation parameter combination is automatically generated by the mathematical optimization algorithm, is sent to the vagus nerve stimulation module through the wireless Bluetooth mode to carry out the stimulation of the next group of stimulation parameters, and the simplex descending method is repeatedly iterated to optimize, so that the vagus nerve stimulation parameter optimization method of finally obtaining the global optimal stimulation parameter combination is formed. Therefore, a stimulation parameter optimization method which can quickly optimize is realized, so as to promote the progress of the animal experiment and convert to the clinical application as soon as possible.

Claims

1. A vagus nerve stimulation device, characterized by, The device comprises a program-controlled instrument (1) and a pulse generator (2); The pulse generator (2) is wirelessly connected with the program-controlled instrument (1) and is used for converting the program-controlled instruction sent by the program-controlled instrument (1) into a fast pacing pulse sequence or a vagus nerve stimulation pulse sequence; The pulse generator (2) is connected with the vagus nerve stimulation electrode (3), the right ventricular photoelectric plethysmography composite electrode (4) and the right ventricular pacing electrode (5) through the electrode interface (27); The vagus nerve stimulation electrode (3) is used for generating a first electric stimulation according to the vagus nerve stimulation pulse sequence; The right ventricular photoelectric plethysmography composite electrode (4) is used for acquiring photoelectric plethysmography data at a set position; The right ventricular pacing electrode (5) is used for generating a second electric stimulation according to the fast pacing pulse sequence, for fast pacing the experimental animal to establish a heart failure model, and for collecting intracavity electrocardiogram data during the first electric stimulation; The pulse generator (2) is used for obtaining cardiovascular physiological parameter data according to the photoelectric plethysmography data, obtaining heart rate detection data according to the intracavity electrocardiogram data, and wirelessly sending the data to the program-controlled instrument (1); The pulse generator (2) comprises a power supply (21) and a microcontroller (22), and a Bluetooth module and an antenna (23), a right ventricular apex fast pacing module (24), a right ventricular blood flow monitoring module (25) and a vagus nerve stimulation module (26) which are respectively connected with the microcontroller (22); The microcontroller (22) is used for converting the program-controlled instruction sent by the program-controlled instrument (1) into corresponding driving pulse parameters; The right ventricular apex fast pacing module (24) is used for converting the program-controlled instruction sent by the program-controlled instrument (1) into a fast pacing pulse sequence, and detecting the heart rate detection data according to the intracavity electrocardiogram data; The right ventricular blood flow monitoring module (25) is used for obtaining cardiovascular physiological parameter data according to the photoelectric plethysmography data; The vagus nerve stimulation module (26) is used for converting the program-controlled instruction sent by the program-controlled instrument (1) into a vagus nerve stimulation pulse sequence; The program-controlled instrument (1) is provided with a stimulation parameter optimization method, comprising: Cardiovascular function parameters of the heart failure animal model after exercise are recorded, including heart rate, respiratory rate, heart rate variability, mixed venous oxygen saturation and maximum rising rate of intraventricular pressure, and a cardiovascular function function is constructed according to the cardiovascular function parameters; a deviation between an actual value and a reference value of the function is calculated; The deviation is mathematically optimized to obtain an optimal vagus nerve stimulation parameter combination; if the actual value of the function corresponding to the initial vagus nerve stimulation parameters does not meet the optimization requirement, a new set of vagus nerve stimulation parameters is randomly generated, the actual value of the function corresponding to the new set of vagus nerve stimulation parameters is calculated, and the mathematical optimization is performed again until the optimal vagus nerve stimulation parameter combination is obtained; The mathematical optimization adopts a simplex down method or an improved simplex down method, and a stimulation parameter combination corresponding to a minimum value of the deviation is the optimal stimulation parameter combination.

2. The vagus nerve stimulation device of claim 1, wherein, The right ventricular apex rapid pacing module (24) comprises a pacing pulse generation unit (241), a pacing pulse emission unit (242), a heart rate detection unit (243), and an intracardiac electrocardio sensing unit (244); The pacing pulse generation unit (241) is configured to generate a corresponding pacing stimulation pulse control signal according to the drive pulse parameters of the microcontroller (22); The pacing pulse emission unit (242) is configured to generate a rapid pacing pulse sequence according to the pacing stimulation pulse control signal and output it; The heart rate detection unit (243) is configured to receive the intracardiac electrocardiogram data collected by the right ventricular pacing electrode (5) and transmit it to the intracardiac electrocardio sensing unit (244); The intracardiac electrocardio sensing unit (244) is configured to detect heart rate detection data from the intracardiac electrocardiogram data and output it to the microcontroller (22).

3. The vagus nerve stimulation device of claim 1, wherein, The right ventricular blood flow monitoring module (25) comprises a drive pulse generation unit (251), a red light drive unit (252), an infrared drive unit (253), a photoplethysmogram detection unit (255), and a physiological parameter detection unit (254); The drive pulse generation unit (251) is configured to generate a corresponding drive pulse control signal according to the drive pulse parameters sent by the microcontroller (22) and transmit it to the red light drive unit (252) and the infrared drive unit (253); The red light drive unit (252) is configured to generate a red light drive signal according to the received drive pulse control signal, and the red light drive signal is delivered to the photoplethysmogram composite electrode (4) through the electrode interface (27) to drive the red light emitting diode therein to emit light; The infrared drive unit (253) is configured to generate an infrared drive signal according to the received drive pulse control signal, and the infrared drive signal is delivered to the photoplethysmogram composite electrode (4) through the electrode interface (27) to drive the infrared light emitting diode therein to emit light; The photoplethysmogram detection unit (255) is connected to the photoplethysmogram composite electrode (4) through the electrode interface (27), receives the red light and infrared light intensity signals detected by the photodiode therein to obtain photoplethysmogram data, and sends it to the physiological parameter detection unit (254); The physiological parameter detection unit (254) detects cardiovascular physiological parameter data from the received photoplethysmogram data and sends it to the microcontroller (22).

4. The vagus nerve stimulation device of claim 1, wherein, The vagus nerve stimulation module (26) comprises a vagus nerve stimulation pulse generation unit (261) and a vagus nerve stimulation pulse emission circuit (262) connected in sequence, The vagus nerve stimulation pulse generation unit (261) is configured to convert the programmed instructions sent by the programmer (1) into a stimulation pulse control signal; The vagus nerve stimulation pulse emission circuit (262) is configured to generate a vagus nerve stimulation pulse sequence according to the stimulation pulse control signal and deliver the stimulation pulse to the vagus nerve stimulation electrode (3) through the electrode interface (27).

5. A vagus nerve stimulation parameter optimization method, characterized by, The vagus nerve stimulation device according to any one of claims 1-4, comprising Obtaining the cardiovascular function parameters of the experimental animal in resting state, and calculating the reference value of the function by a preset cardiovascular function function; According to the distribution of each vagus nerve stimulation parameter, a vagus nerve stimulation parameter combination is randomly selected as the initial vagus nerve stimulation parameter; Obtaining the intracavity electrocardiogram data and the photoplethysmogram data during the vagus nerve stimulation according to the initial vagus nerve stimulation parameter after the exercise of the heart failure animal model, and calculating the actual value of the function by the preset cardiovascular function function; Calculating the deviation between the actual value of the function and the reference value of the function, and mathematically optimizing the deviation to obtain the optimal vagus nerve stimulation parameter combination; if the actual value of the function corresponding to the initial vagus nerve stimulation parameter does not meet the optimization requirement, a new vagus nerve stimulation parameter combination is randomly generated, the actual value of the function corresponding to the new vagus nerve stimulation parameter combination is calculated, and the mathematical optimization is performed again until the optimal vagus nerve stimulation parameter combination is obtained; The mathematical optimization adopts the simplex down method or the improved simplex down method, and the stimulation parameter combination corresponding to the minimum value of the deviation is the optimal stimulation parameter combination.

6. The method of vagus nerve stimulation parameter optimization of claim 5, wherein, The preset cardiovascular function function is as follows, ； in, for Cardiovascular function value at time; The heart rate at time t; This is the reference value for heart rate at normal resting time; Let be the respiratory rate at time t; The respiratory rate is the reference value for normal resting conditions. Heart rate variability at time t; This is a reference value for heart rate variability at normal resting time; The mixed venous oxygen saturation at time t; This is a reference value for mixed venous oxygen saturation at normal resting conditions. The maximum rate of increase of intracardiac pressure at time t; This is a reference value for the maximum rate of increase in indoor pressure under normal resting conditions; ~ is the proportional factor for each term.

7. The method of vagus nerve stimulation parameter optimization of claim 5, wherein, The one vagus nerve stimulation parameter combination at least includes five of the current amplitude, the voltage amplitude, the pulse width, the pulse delay, the pulse duration, the output pulse number and the pulse interval.

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