Porta nerve plexus nerve stimulator for increasing blood sugar

Abstract

The invention discloses a portal nerve plexus nerve stimulator for increasing blood sugar. The portal nerve plexus nerve stimulator comprises a pulse generator and an electrode, the pulse generator is programmed to guide a pulse electrical signal at a frequency of 1 kHz to 10 kHz, an amplitude of 0.1 mA to 10 mA and a pulse width of 10 microseconds to 50 microseconds; one end of the electrode can be implanted into the porta hepatis nerve plexus part of a subject, the other end of the electrode is connected with one end of the pulse generator, and the pulse generator is used for receiving a pulse signal and performing electrical stimulation at the electrode based on the received pulse signal. When the portal nerve plexus nerve stimulator is adopted to stimulate the portal nerve plexus, the blood glucose level of a subject can be remarkably increased.

Description

Technical Field

[0001] The invention relates to the technical field of medical devices, and in particular to a portal plexus nerve stimulator for increasing blood sugar. Background Art

[0002] Neuromodulation technology is a method that uses the nervous system to regulate body functions. It regulates physiological processes by intervening in nerve signal conduction or activity. This technology includes a variety of methods, such as electrical stimulation, optogenetics, and acoustic stimulation. Neuromodulation technology has been widely studied and applied in many fields, such as pain management, neurological disease treatment, and metabolic regulation. However, the mechanism of neuromodulation in human blood sugar regulation has not yet been studied, discovered, or applied. Summary of the invention

[0003] The object of the present invention is to provide a portal plexus nerve stimulator for increasing blood sugar.

[0004] The portal plexus nerve stimulator for increasing blood sugar provided by the present invention comprises a pulse generator and an electrode; The pulse generator is programmed to direct a pulsed electrical signal at a frequency of 1 kHz to 10 kHz, an amplitude of 0.1 mA to 10 mA, and a pulse width of 10 microseconds to 50 microseconds; One end of the electrode can be implanted in the portal plexus of the subject, and the other end is connected to one end of the pulse generator for receiving a pulse signal and performing electrical stimulation at the electrode based on the received pulse signal.

[0005] In some embodiments, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1 kHz to 5 kHz, an amplitude of 0.1 mA to 10 mA, and a pulse width of 10 microseconds to 50 microseconds.

[0006] In some embodiments, the pulse generator is programmed to direct the pulsed electrical signal at a frequency of 5 kHz to 10 kHz, an amplitude of 0.1 mA to 10 mA, and a pulse width of 10 microseconds to 50 microseconds.

[0007] In some embodiments, the pulse generator is programmed to deliver a single electrical stimulation to the subject's portal plexus for at least 1-5 min.

[0008] In some embodiments, the pulse generator is programmed to provide periodic continuous stimulation to the subject's portal plexus.

[0009] In some embodiments, the pulse generator is programmed to electrically stimulate the portal nerve plexus of the subject for 24 hours and then cease electrical stimulation for 48 hours as a cycle.

[0010] In some embodiments, the neurostimulator further comprises: a programmer for sending instructions to the pulse generator, and the pulse generator is used to determine the frequency and duration to be output according to the instructions.

[0011] In some embodiments, the neurostimulator further comprises a wireless power supply for wirelessly supplying power to the pulse generator.

[0012] In some embodiments, the pulse generator includes machine-readable data comprising instructions for generating and delivering therapeutic signals.

[0013] In some embodiments, the pulse generator may also receive and respond to input signals from one or more sources.

[0014] Stimulating the portal nerve plexus with the portal nerve plexus nerve stimulator of the present application can significantly increase the blood sugar level of the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1a and Figure 1b Shown are the results of intravenous glucose tolerance tests in SD rats.

[0016] Figure 2 The graph shows the 24-hour blood glucose monitoring results of Bama Xiang pigs under 1 Hz-100 Hz electrical stimulation.

[0017] Figure 3 The results of 24-hour blood glucose monitoring of Bama Xiang pigs under 1kHz-10kHz electrical stimulation are shown.

[0018] Figure 4 The c-fos detection results of SD rats are shown.

[0019] Figure 5 The results of the peak increase rate of blood glucose in Bama Xiang pigs under 1kHz-10kHz electrical stimulation are shown.

[0020] Figure 6 The results of the blood glucose peak reduction rate of Bama Xiang pigs under 10Hz-100Hz electrical stimulation are shown.

[0021] Figure 7 The figure shows the 24-hour blood glucose curve of the patient after receiving 24-hour continuous high-frequency band stimulation.

[0022] Figure 8 The figure shows the 24-hour blood glucose curve of the patient after receiving 24-hour low-frequency continuous stimulation.

[0023] Fig. 9 The results of the peak increase rate of blood glucose in patients receiving 1kHz-10kHz electrical stimulation are shown.

[0024] Fig.10 The results show the peak blood glucose reduction rate of patients receiving 1Hz-100Hz electrical stimulation.

[0025] Fig.11 Photographs showing the surgical procedure to implant a neurostimulator.

[0026] Fig.12 A schematic diagram of a neurostimulator, in one embodiment, is shown.

[0027] Fig.13 A schematic diagram of a neurostimulator in yet another embodiment is shown.

[0028] Fig.14 A schematic diagram of a neurostimulator in another embodiment is shown.

[0029] Fig.15 A schematic diagram of a neurostimulator in yet another embodiment is shown. DETAILED DESCRIPTION

[0030] In order to better illustrate the purpose, complete technical route and advantages of the present invention, the present invention will be further described in detail below in conjunction with specific embodiments and drawings. However, the embodiments described below are only part of the embodiments of the present invention and do not include all the embodiments. Based on the embodiments of the present invention, other embodiments that can be obtained by those skilled in the art without paying creative work all belong to the protection scope of the present invention.

[0031] In the embodiments described below, unless otherwise specified, the conventional methods used are technical means generally recognized or commonly used by those skilled in the art, and the instruments, reagents, consumables, etc. used in the embodiments of the present invention can be obtained through regular commercial channels.

[0032] Too high or too low blood sugar can cause health problems. Currently, the medical community is focused on lowering blood sugar, and the main way is to rely on drugs. There are no other mature regulatory methods clinically.

[0033] In order to overcome the above problems, the medical community has conducted a lot of exploration. The medical community has found that medical treatments targeting the portal plexus, celiac vagus nerve, pancreatic sympathetic nerves and other parts can lower blood sugar.

[0034] For example, among the medical explorations most relevant to the present application, one is the article "Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine" conducted by Cotero et al. in the journal Nature Biomedical Engineering in 2022, which conducted a peripheral focused ultrasound stimulation (pFUS) experiment on the portal nerve plexus. Cotero et al. found that when the portal nerve plexus was stimulated with ultrasound under the parameter selection of 1.1Mhz carrier, 135mV peak signal generation amplitude, 150us pulse duration, and 5Hz pulse repetition frequency, the tested experimental subjects showed reproducible blood sugar reduction.

[0035] The second is the study conducted by Waataja et al. in the paper "Use of abio-electronic device comprising of targeted dual neuromodulation of thehepatic and celiac vagal branches demonstrated enhanced glycemic control in atype 2 diabetic rat model as well as in an Alloxan treated swine model" published in the journal "Frontiers in Neuroscience" in 2022. By simultaneously stimulating the abdominal vagus nerve with an amplitude of 8 mA, a pulse width of 4 ms, and a frequency of 1 Hz, and stimulating the hepatic vagus nerve with an amplitude of 8 mA, a pulse width of 90 μs, and a frequency of 5,000 Hz, that is, by performing electrical stimulation tests on the liver and abdominal vagal branches, Waataja et al. found that the glucose tolerance of the subjects was significantly improved, which was manifested as a decrease in blood sugar.

[0036] In summary, the medical community has only discovered the electrical stimulation regulatory mechanism for the hepatic vagus nerve and the pFUS regulatory mechanism for the portal plexus, and has only discovered the regulatory mechanism of the two in lowering blood sugar; the medical community has not conducted neuroregulatory research based on electrical stimulation on the portal plexus, nor has it discovered any regulatory mechanism that can increase blood sugar through stimulation in all other stimulation areas, including electrical stimulation and pFUS.

[0037] Based on the above research conducted by the medical community, the applicant conducted a large number of experimental studies and applied the new mechanism discovered through the medical device of electrical nerve stimulator. The applicant emphasizes that the purpose of describing the current status of the above research in the medical community is to explain that current researchers have not conducted research in the field of electrical stimulation of the portal nerve plexus, and there is no motivation to conduct conventional parameter selection in this field to achieve, let alone select certain parameters to achieve the increase of blood sugar.

[0038] The following explains the medical device products provided by the applicant: The portal plexus nerve stimulator for regulating blood sugar provided by the present application comprises a pulse generator and an electrode; The pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1 kHz to 10 kHz, an amplitude of 0.1 mA to 10 mA, and a pulse width of 10 microseconds to 50 microseconds; One end of the electrode can be implanted in the portal plexus of the subject, and the other end is connected to one end of the pulse generator for receiving a pulse signal and performing electrical stimulation at the electrode based on the received pulse signal.

[0039] In one embodiment, the pulse generator is programmed to guide the pulse electrical signal at a frequency of 1kHz to 5kHz, an amplitude of 0.1mA to 10mA, and a pulse width of 10 microseconds to 50 microseconds. At a frequency of 1kHz to 5kHz, the blood sugar raising effect is already obvious, and for the subject, the blood sugar raising range is relatively gentle, avoiding a sharp rise and fall of blood sugar, which is safer.

[0040] In some embodiments, the pulse generator is programmed to guide the pulse electrical signal at a frequency of 5kHz to 10kHz, an amplitude of 0.1mA to 10mA, and a pulse width of 10 microseconds to 50 microseconds. At a frequency of 5kHz to 10kHz, the blood glucose peak increase rate increases rapidly, and the blood glucose lifting and lowering efficiency is high.

[0041] The pulse generator and the electrode as devices themselves and the connection relationship between the two are consistent with the prior art and are not the focus of this application. This application only provides a general description.

[0042] The pulse generator can be implanted subcutaneously in the patient's body or can be hung externally on the patient's body; as long as the electrical stimulation generated by the pulse generator can be smoothly transmitted to the patient's portal plexus nerves through the electrodes.

[0043] In general, the pulse generator may include machine-readable data containing instructions for generating and sending suitable therapeutic signals. Other elements of the pulse generator may include one or more processors, memories and / or input-output devices. Accordingly, the process of providing a modulation signal and performing other related functions may be performed by computer-executable instructions contained on a computer-readable medium. The pulse generator may include multiple parts, elements and / or subsystems (e.g., for guiding signals according to multiple signal delivery parameters). The pulse generator may also receive and respond to input signals derived from one or more sources. The input signal may guide or influence the manner in which the therapeutic instruction may be selected, executed, updated and / or otherwise executed.

[0044] The pulse generator may obtain energy from an external power source to generate the therapeutic signal. In another embodiment, in addition to or in lieu of the external power source, the pulse generator may obtain energy from an internal power source to generate the therapeutic signal. For example, the implanted pulse generator may include a non-rechargeable battery or a rechargeable battery to provide such energy. When the internal power source includes a rechargeable battery, the external power source may be used to charge the battery. The external power source may be charged from a suitable power source in turn.

[0045] Specifically, if Fig.12 As shown, in one embodiment, the neurostimulator includes: a pulse generator, an electrode wire that is detachably electrically connected to the pulse generator, and an electrode disposed at the end of the electrode wire. In this embodiment, the electrode wire is implanted in the patient's body, and the electrode is close to the neural target point, so that the neural target point can be stimulated by outputting an electrical stimulation signal through the pulse generator attached to the human skin. The advantage of adopting this embodiment is that it has a small wound for the patient, can be implanted for a short period of time, and can treat the corresponding disease in a shorter period of time; it can also be used to test the effectiveness of the treatment before the long-term stimulator is implanted.

[0046] like Fig.13 As shown, in one embodiment, the neurostimulator is a fully implantable neurostimulator. The pulse generator has a battery and a receiving coil, which are implanted in the human body together with the neurostimulation electrode for operation. The external power supply uses the transmitting coil to supply power after the power inside the pulse generator is consumed to keep the neurostimulator working. The advantage of adopting this embodiment is that the pulse generator can be implanted in the body for a long time, reducing the impact on the patient's daily life. It only needs to be powered by a charger (not shown) after the power is consumed.

[0047] like Fig.14As shown, in one embodiment, the neurostimulator is a fully implantable neurostimulator. The pulse generator does not use batteries for energy storage. The energy storage unit is a capacitor, and it needs to be continuously wirelessly powered by a matching wireless power supply device placed outside the human body to realize the operation of the pulse generator. The advantage of adopting this embodiment is that since there is no battery inside the pulse generator, the size of the pulse generator implanted in the human body is greatly reduced, the implantation wound is smaller, and the safety is also higher; in addition, it also solves the problem of battery cycle life. After the battery cycle life is exhausted, the battery of the external power supply device can be replaced without the need for surgical removal.

[0048] like Fig.15 As shown, in one embodiment, the neurostimulator is a fully implantable neurostimulator. Fig.14 The embodiment shown reduces electrode wires, and the electrodes are directly set on the pulse generator. During implantation, the pulse generator is directly placed near the target nerve to stimulate the target nerve.

[0049] The applicant conducted an electrical stimulation test on animals under the above parameter selection. The applicant needs to explain that in the research field of neural regulation, animal experiments and human experiments have shown extremely good consistency, and the parameters of animal experiments are generally recognized to be directly used in clinical practice.

[0050] For example, in “Yuan, H., Lin, JK,&Wang, WD (2016). Effect of transcutaneous vagus nerve stimulation in a chronic feline epilepsymodel study. Brain Stimulation, 9(6), 796-803", "Campbell, JN, & Meyer, RA(2006). Mechanisms of neuropathic pain. Neuron, 52(1), 77-92", "Fregni, F., Boggio, PS, Lima, MC, Ferreira, MJ, Wagner, T., Rigonatti, SP,... & Pascual-Leone, A. (2006). A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of depression. Neurology, 66(6), 448-450", "Song, Z., Ultenius, C., Meyerson, BA, Linderoth, B. (2009). Pain relief by spinal cord stimulation involves serotonergic mechanisms: An experimental study in a rat model ofmononeuropathy. Pain, 147(1-3), 241-248” and many other literatures have been well verified.

[0051] To this end, the applicant has repeatedly conducted the following animal experiments: SD rat experiments 1. Rat Surgical Procedure After the rat is anesthetized, the abdominal cavity of the rat is opened to expose the hepatic hilum. The stimulating electrode is fixed at the hepatic hilum. Fig.11 (left picture) shown.

[0052] 2. Intravenous Glucose Tolerance Test (IVGTT) This experiment is used to test the glucose metabolism ability of rats. The specific operation is to give rats an intravenous injection of 500 mg / Kg of glucose under anesthesia and then test the blood sugar fluctuations of the rats within two hours. Each IVGTT test lasts for 2 hours.

[0053] 3. Portal plexus stimulation Before the stimulation started, the rats were subjected to an IVGTT test to obtain a baseline value of glucose tolerance. Then, the rats were stimulated with portal nerve plexus stimulation (high frequency / low frequency, uninterrupted stimulation) for 5 minutes and subjected to a second IVGTT test. After the test, the stimulation was turned off.

[0054] 4.c-fos detection Immediately after the stimulation, the SD rats were perfused and fixed with 4% paraformaldehyde, and then the liver tissues were taken out and the c-fos was detected by ELISA.

[0055] Bama Xiang pig experiment 1. Surgical Procedure After general anesthesia, the experimental pigs were implanted with stimulation electrodes in the liver portal area, and an adjustable current pulse generator was implanted subcutaneously in the abdomen. Fig.11 As shown in the figure on the right, a 24-hour blood glucose monitoring device (CGM) was installed on the left back of the pig.

[0056] 2. Blood glucose monitoring The experimental pigs were fed a fixed amount of food and time throughout the whole process. The experimental pigs were placed in a 3-day cycle mode, "no stimulation for 2 days, then stimulation for 24 hours (uninterrupted stimulation)", and the blood sugar changes were recorded.

[0057] Experimental Results like Figure 1a and Figure 1b As shown in the figure, from the results of intravenous glucose tolerance test of SD rats, it can be seen that 1Hz-10Hz electrical stimulation can significantly reduce the peak blood glucose level to below the baseline level; while 1kHz-10kHz electrical stimulation can significantly increase the peak blood glucose level, exceeding the baseline level.

[0058] c-fos is a protein marker commonly used in neuroscience research to detect neuronal activity. Figure 4 As shown, the c-fos detection results of rats showed that the portal nerve plexus receiving current stimulation in the frequency range of 1Hz-100Hz can activate the neuronal activity of the portal nerve plexus, and the neuronal activity of the portal nerve plexus receiving current stimulation in the frequency range of 1kHz-10kHz can be inhibited (data are mean ± standard deviation).

[0059] The same phenomenon was further verified in live pigs. Figure 2As shown in the figure, the 24-hour blood glucose monitoring instrument of live pigs showed that under 10Hz-100Hz electrical stimulation, the 24-hour blood glucose of the experimental pigs was significantly lower than the baseline. Figure 3 As shown, under the electrical stimulation frequency of 1kHz-10kHz, the 24-hour blood glucose of the experimental pigs was significantly increased.

[0060] Since high frequency has an inhibitory effect on nerve transmission, as the frequency increases, the inhibitory effect of electrical stimulation becomes stronger. Figure 5 As shown in the figure, the blood sugar increase effect starts at 1kHz, and as the frequency increases, the blood sugar peak increase rate increases. At 7kHz, the blood sugar peak increase rate has reached about 70%; at 10kHz, the blood sugar increase rate has exceeded 120%. Figure 5 The increase rate = (the highest blood glucose value measured in the test frequency band - the highest baseline blood glucose value) / the last baseline blood glucose value * 100%.

[0061] like Figure 6 As shown in the figure, under the electrical stimulation of 1Hz-50Hz, the peak blood glucose reduction rate gradually increased, and the peak blood glucose reduction rate exceeded 20% at 1Hz. The effect of lowering blood sugar was better at 30Hz-70Hz, and the peak blood glucose reduction rate exceeded 40% at 30Hz and 70Hz. Under the electrical stimulation of 50Hz-100Hz, the peak blood glucose reduction rate gradually decreased, and the peak blood glucose reduction rate at 10Hz and 100Hz was equivalent, and the peak blood glucose reduction rate still reached about 20%. Figure 6 Reduction rate = (maximum value of baseline blood glucose) - (maximum value of blood glucose measured in the test band) / final value of baseline blood glucose * 100%.

[0062] In order to further verify the accuracy of the animal experiments, the applicant also conducted the following human clinical experiments with a cautious attitude.

[0063] Clinical Trials Experiment of increasing blood sugar in patients with frequent hypoglycemia 1. Surgical Procedure After the patient was given general anesthesia, a stimulating electrode was implanted in the liver hilum, an adjustable current pulse generator was implanted subcutaneously in the abdomen, and a 24-hour blood glucose monitoring device (CGM) was installed on the patient's buttocks.

[0064] 2. Blood glucose monitoring The patient's diet and time were fixed throughout the whole process. First, the program controller was turned off for one week to record the patient's basal blood sugar value (baseline), and then the patient was turned on for 2 weeks of programming. During the programming period, the high frequency band was used for continuous stimulation and parameter adjustment. After the ideal blood sugar was obtained during the test, the fixed degree parameters were used for continuous stimulation and the blood sugar value (1kHz-10kHZ) was recorded for one week.

[0065] like Figure 7 As shown, the baseline is the normal 24-hour blood glucose curve of patients with frequent hypoglycemia, and 1kHz, 5kHz, and 10kHz are the 24-hour blood glucose curves after receiving 24-hour high-frequency continuous stimulation. Under the electrical stimulation frequency of 1kHz-10kHz, the patient's 24-hour blood glucose increased significantly.

[0066] like Fig. 9 As shown in the figure, the blood sugar increase effect starts at 1kHz, and the blood sugar peak increase rate increases with the increase in frequency. At 3kHz, the blood sugar peak increase rate exceeds 20%, at 7kHz, the blood sugar peak increase rate has reached about 60%, and at 10kHz, the blood sugar increase rate has exceeded 100%.

[0067] Experiment on lowering blood sugar in diabetic patients 1. Surgical Procedure After the patient was given general anesthesia, a stimulating electrode was implanted in the liver hilum, an adjustable current pulse generator was implanted subcutaneously in the abdomen, and a 24-hour blood glucose monitoring device (CGM) was installed on the patient's upper buttocks.

[0068] 2. Blood glucose monitoring The patient's diet and time were fixed throughout the whole process. First, the program controller was turned off for one week to record the patient's basal blood sugar value (baseline), and then the patient was turned on for 2 weeks of programming. During the programming period, low-frequency bands were used for continuous stimulation and parameter adjustments were made. After the ideal blood sugar was obtained during the test, the program parameters were fixed for continuous stimulation and the blood sugar value (1Hz-100Hz) was recorded for one week.

[0069] like Figure 8 As shown in the figure, the baseline is the normal 24-hour blood sugar curve of diabetic patients, and 1Hz, 30Hz, 70Hz, and 100Hz are the 24-hour blood sugar curves after receiving low-frequency continuous stimulation. Under the electrical stimulation frequency of 1Hz-100Hz, the patient's 24-hour blood sugar is significantly reduced.

[0070] like Fig.10 As shown in the figure, under 1Hz-50Hz electrical stimulation, the blood glucose peak reduction rate gradually increased. The blood glucose reduction effect was better at 30Hz-70Hz electrical stimulation, and the blood glucose peak reduction rate exceeded 50% at 30Hz and 70Hz. Under 50Hz-100Hz electrical stimulation, the blood glucose peak reduction rate gradually decreased, and the blood glucose peak reduction rate exceeded 10% at 1Hz, and the blood glucose peak reduction rate at 100Hz was still more than 20%.

[0071] The applicant believes that the above phenomenon can be explained by the following mechanism: the portal plexus can obtain the blood glucose level signal monitored by the surrounding hepatocytes and transmit it upward to the hypothalamus. After the portal neurons receive different means of neuroregulation (activation / inhibition) of neuronal activity. The activated portal plexus has an increased discharge frequency, which transmits to the hypothalamus a blood glucose signal that is higher than the blood glucose signal (basal value) monitored by hepatocytes; conversely, in the inhibited portal plexus, the excitability of neurons in this area is inhibited, and its discharge frequency is reduced, thereby transmitting to the hypothalamus a blood glucose signal that is lower than the blood glucose signal (basal value) monitored by hepatocytes. The neurons in the arcuate nucleus (ARC) of the hypothalamus can recognize the blood glucose signal, and the POMC neurons and AgPR neurons in the ARC can regulate appetite to affect feeding behavior to regulate blood glucose. And the ARC neurons can further transmit the blood glucose signal to the paraventricular nucleus neurons (PVN) in the hypothalamus, which is the regulatory center of the neuroendocrine system.

[0072] PVN can regulate related glucose metabolism pathways by secreting a variety of neuroendocrine hormones: (1) Hypothalamic-pituitary-adrenal cortisol axis (HPA axis): PVN can secrete corticotropin-releasing hormone (CRH), which can stimulate the anterior pituitary to release adrenocorticotropic hormone (ACTH), thereby affecting the adrenal cortex to secrete cortisol. Cortisol is an important stress hormone that can promote glucose production and release, thereby increasing blood sugar levels. (2) Hypothalamic-pituitary-thyroid axis (HPT axis): PVN can secrete thyrotropin-releasing hormone (TRH), which can stimulate the anterior pituitary to release thyrotropin (TSH), which in turn stimulates the thyroid gland to secrete thyroxine. Thyroxine can increase insulin sensitivity and promote glucose utilization, thereby regulating blood sugar levels.

[0073] In summary, the applicant proposed that 1kHz-10kHz current stimulation of the portal nerve plexus can significantly increase blood sugar levels to solve the problem of low blood sugar; 1Hz-100Hz current stimulation of the portal nerve plexus can significantly reduce blood sugar peaks to solve the problem of high blood sugar.

Claims

1. A neural stimulator for increasing blood sugar, comprising a pulse generator and an electrode; The pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1 kHz to 10 kHz, an amplitude of 0.1 mA to 10 mA, and a pulse width of 10 microseconds to 50 microseconds; One end of the electrode can be implanted in the portal plexus of the subject, and the other end is connected to one end of the pulse generator for receiving a pulse signal and performing electrical stimulation at the electrode based on the received pulse signal.

2. The neurostimulator according to claim 1, It is characterized in that The pulse generator is programmed to direct the pulsed electrical signal at a frequency of 1 kHz to 5 kHz, an amplitude of 0.1 mA to 10 mA, and a pulse width of 10 microseconds to 50 microseconds.

3. The neurostimulator according to claim 1, It is characterized in that The pulse generator is programmed to direct the pulsed electrical signal at a frequency of 5 kHz to 10 kHz, an amplitude of 0.1 mA to 10 mA, and a pulse width of 10 microseconds to 50 microseconds.

4. The neurostimulator according to any one of claims 1 to 3, It is characterized in that The pulse generator is programmed to deliver a single electrical stimulation to the subject's portal plexus for at least 1-5 min.

5. The neurostimulator according to any one of claims 1 to 3, It is characterized in that The pulse generator is programmed to provide periodic and continuous stimulation to the subject's portal plexus.

6. The neurostimulator according to claim 5, It is characterized in that The pulse generator is programmed to electrically stimulate the portal nerve plexus of the subject for 24 hours and then stop electrically stimulating the subject for 48 hours as a cycle.

7. A neurostimulator according to any one of claims 1 to 3, It is characterized in that The neural stimulator further comprises: a programmer, which is used to send instructions to the pulse generator, and the pulse generator is used to determine the frequency and duration to be output according to the instructions.

8. The neurostimulator according to any one of claims 1 to 3, It is characterized in that The neural stimulator also includes a wireless power supply device for wirelessly supplying power to the pulse generator.

9. The neurostimulator according to any one of claims 1 to 3, It is characterized in that The pulse generator includes machine-readable data comprising instructions for generating and delivering therapy signals.

10. The neurostimulator according to any one of claims 1 to 3, It is characterized in that The pulse generator may also receive and respond to input signals from one or more sources.

Images