WO2015168821A2

WO2015168821A2 - The application of high frequency current in treating obstructive sleep apnea syndrome

Info

Publication number: WO2015168821A2
Application number: PCT/CN2014/000537
Authority: WO
Inventors: 李明娴; 康晶; 王晶华; 王绍
Original assignee: 吉林大学
Priority date: 2014-05-05
Filing date: 2014-05-28
Publication date: 2015-11-12
Also published as: CN103949010A

Description

Technical field

The invention belongs to the technical field of respiratory medicine, neurosurgery and neuroelectrophysiology, and relates to the application of high frequency current in the treatment of obstructive sleep apnea syndrome.

Background technique

Obstructive sleep apnea syndrome (OSA) has a significantly higher rate of hypertension, myocardial infarction, arrhythmia, and cerebrovascular accident than non-OSA. In the case of arrhythmia, the incidence of atrial fibrillation in patients with severe OSA was 5 %, and the incidence of atrial fibrillation in patients with apnea hypopnea was more than 30. In addition, chronic intermittent tissue hypoxia in children with OSA causes insulin resistance in patients, induces childhood obesity and abnormal glucose metabolism, affects children's mental development and advances the onset age of cardiovascular and cerebrovascular diseases. Treatment of OSA helps reduce the incidence of cardiovascular and cerebrovascular diseases.

The new concept of "insular cortex (Ic) is the cortical representative region of OSA onset" was first proposed by Professor Wang Shao, a famous neurophysiologist in China. When applying for a doctoral degree, the applicant of the project, under the auspices of Professor Wang Shao, under the support of the National Natural Science Foundation of China (Project Approval Number: 30270502), established the OSA animal model based on this concept. In this model, we used electrokinetic stimulating rat island leaf cortex, and the habenular (Hb) neurons showed increased discharge, respiratory disorders and apnea, decreased geniogyomyosin, and decreased arterial blood pH. Acidosis, etc. When the above changes occur in the animal, the brainstem is taken (the brain region where the nucleus is located) to detect 5-HT, and the brain stem neurons are fine. Intracellular 5-HT was significantly reduced. These changes are consistent with the pathophysiological changes of OSA patients, and the work has been recognized by domestic and foreign counterparts.

Oades et al. showed that the mesolimbic is the important neural pathway that connects and regulates the activity of neurons in the forebrain-edge system and central autonomous network. The central nucleus of the loop includes the island cortex and the nucleus. (habenular nucleus) and the central structure of the nucleus, involving the survival mechanism of individuals, closely related to the stability of the internal environment, respiratory index and nighttime minimum oxygen saturation in OSA patients, maximal collapse of upper airway and pharyngeal vector The transverse diameter ratio is closely related, that is, the greater the airway collapse degree (compliance), the more severe the sleep-disordered breathing, and the lower the arterial oxygen saturation. Studies have shown that the maximal collapse of the upper airway and the ratio of the lingual vaginal vector/transverse diameter to the central nervous system respiratory drive and the genioglossus

(genioglossus, GG) Functional changes are closely related. GG is the most important pharyngeal muscle. When the genioglossus contraction function is weakened, the pharyngeal cavity collapses or is completely occluded, and snoring or breathing pauses. The intermittent anoxic OSA animal model showed a marked decrease in the electrical activity of the genioglossus muscle.

In peripheral tissues, 5-HT is a strong vasoconstrictor and smooth muscle contraction stimulator. It must be mediated through the corresponding receptors, and its receptor typing is complex. According to current molecular biology and pharmacology research, there are at least 7 types of human 5-HT receptors. Can be further divided into several subtypes. 5-HT can have different effects by stimulating different types of 5-HT receptors. With the deepening of OSA research, the role of 5-HT in the pathogenesis of OSA has attracted more and more attention: GG is dominated by the twelfth pair of cranial nerves - the sublingual nerve, and the neurotransmitter is serotonin (5-hydroxytryptamine). , 5-HT). However, the role of 5-HT in the physiological functions of the nucleus is of little concern.

5-HT in the body is mainly derived from the nucleus raphe magnus, The nucleus is the superior nerve center of the central nucleus. The level of nuclear activity in the nucleus is affected by the nucleus activity, which regulates the release of 5-HT from the nucleus raphe by continuous inhibition. When 5-HT is reduced in the central nervous system, the 5-HT concentration of the axonal transport to the sublingual ganglia of the sublingual nucleus is reduced, which may lead to a decrease in genioglossus contraction, which is the main cause of OSA. Among the various subtypes of 5-HT, 2A and 2C have the most obvious effect on GG, and the longest action time.

Respiratory exercise is simultaneously controlled by the brainstem autonomic center and the cerebral cortex. Imaging studies have found that functional nuclear magnetic (fMRI) signals in the cerebral cortex of OSA patients have significant abnormal changes in the anterior islets. Damage to the insular cortex of rats can alleviate the difficulty of breathing in rats, indicating that the occurrence of dyspnea is closely related to the activity of the insular cortex, and further supports the theory that "the island cortex is the representative area of the OSA cortex." Therefore, it is a reasonable choice to explore the pathogenesis of OSA by directly observing the leaf layer of the irritating island and observing the effects on respiratory movement and respiratory related indicators.

Based on the above theory, we performed electroconvulsive excitation of insular island neurons in the insular cortex of rats, causing respiratory disorders, apnea, decreased GG electrical activity, reduction of central 5-HT, and decreased arterial blood pH. The OSA animal model also confirms the correctness of the above imaging and experimental studies.

To date, the world's recognized effective treatment for OSA is continuous positive airway pressure (CPAP), but the following reasons limit the application of CPAP: CPAP cannot treat OSA fundamentally or from the pathogenesis. This is the most The important shortcomings; secondly, the patient's fear, the price of the machine is expensive, the home machine medical insurance can not be reimbursed, so that the family application is limited, especially the patients with indications in the primary hospital often refuse to buy the ventilator due to economic reasons, resulting in the disease not being obtained. Proper treatment Delayed the condition. Followed by surgery, because the recurrence rate of the disease is very high, in addition to the destruction of local tissue, postoperative patients still need CPAP ventilator treatment. Therefore, fundamentally treating OSA still needs to start from the pathogenesis of the disease.

Summary of the invention

The present invention provides the use of high frequency currents in the treatment of obstructive sleep apnea syndrome, and is also characterized by the use of high frequency current stimulation of the nucleus to treat obstructive sleep apnea syndrome. The high-frequency current parameter is 50-150uA, the frequency is 50-280HZ, and the wave width is 0.3ms square wave; the 缰缰缰 time is 30 minutes.

The invention has the advantages that: the middle nucleus releases more 5-HT, promotes the contraction of the genioglossus muscle, enlarges the pharyngeal cavity, achieves the purpose of treating OSA and fundamentally eliminates OSA, and wears a ventilator and surgery. upset.

DRAWINGS

Figure 1 is a graph showing changes in the respiratory motion of insular cortex in rats after electrical stimulation and glutamate stimulation before and after blocking the nucleus;

Figure 2 is a graph showing the changes of GG myoelectricity in the insular cortex of rats after sputum nucleus stimulation. detailed description

The invention will be described in detail below with reference to the drawings and specific embodiments.

The invention relates to the application of high frequency current in the treatment of obstructive sleep apnea syndrome. High frequency current is used to stimulate the nucleus to treat obstructive sleep apnea syndrome. The high-frequency current parameter is 50-150uA, the frequency is 50-280Hz, and the wave width is a square wave of 0.3ms; the excitation nucleus time is 30 minutes.

The invention is verified, and the nucleus is targeted on the basis of the animal model, and the application is high. Frequent electrical stimulation inhibited rat nucleus neurons, increased excitability of central nucleus neurons, and increased central endogenous 5-HT transmitter secretion.

The nucleus is an important structure for the control of 5-HT. It regulates the release of monoamine neurotransmitters including 5-HT in the brain through sustained inhibition of the nucleus. The nucleus of the nucleus in the upper cerebral cortex is the insular, and the insular neurons are excited, which will cause the excitability of the lower nucleus neurons. Once the level of nucleus activity in equilibrium is increased, the inhibitory effect on the nucleus raphe nucleus will be enhanced, and the release of 5-HT will decrease, resulting in weakened genioglossus contraction, pharyngeal stenosis, occlusion, and apnea. The results of animal experiments show that when the rats have apnea, the nucleus is in an excited state, and its activity level is very high, which is caused by the abnormal excitation of the insular cortex. As the excitability of the insular cortex of the upper nucleus of the nucleus of the nucleus, it is bound to cause an increase in the excitability of the nucleus, which further strengthens the inhibition of the nucleus of the nucleus of the lower nucleus, resulting in a decrease in the release of 5-HT and a decrease in the electrical activity of the genioglossus. The contraction function is weakened, causing the pharyngeal cavity to collapse or occlude, and apnea occurs. After the nucleus was blocked, these changes no longer occurred and the animals breathed smoothly. Therefore, inhibiting the level of deuterium activity may become a new means of treating OSA. This is the basis for our proposed high-frequency electrical stimulation of the nucleus in this topic.

The significance of the present invention is to propose and preliminarily prove that "the insular cortex is the cortical representative region of the onset of OSA, and the habenular nucleus is the inevitable path for signal transduction of the insular cortex." The present invention uses the high-frequency electrical stimulation of the nucleus to further reveal the conduction pathway and neurotransmitter of the OSA cortex signal. Based on the previous research results, the 5-HT and its subtypes of the central nervous system in OSA are further explored. Changes and their effects on the electrical activity and respiratory movement of the genioglossus provide a theoretical basis for opening up new approaches to OSA treatment.

Step 1: Fix the anesthetized animal on the VDT-1 brain stereotactic device with an ear stick. Cut the epidermis to expose the skull near the midline. Insert the helium nucleus with a concentric electrode. The nucleus coordinates are

AP: -3.4, L: 0.6, H: 5.3. The rats in the experimental group were electrically stimulated by a stimulating electrode (outer diameter 2.0 mm, 2 to 5 Μ Ω) which was previously embedded in the nucleus.

Step 2: Use high-frequency current to stimulate the nucleus (stimulus parameters: current intensity 50-150uA, frequency 50-280Ηζ, square wave with a width of 0.3ms, lasting 30 minutes.

Step 3: Record respiratory movement, GG electromyography and diaphragm electromyography: Connect the largest part of the rat's abdominal breathing to the tension amplifying device, and output the signal to the BL-420E + biological skill experiment system to trace the respiratory motion curve of the rat. . Changes in respiratory amplitude and frequency are used as objective indicators of respiratory motion. While recording the respiratory movement, the concentric electrode was inserted into the rat GG muscle piece and the diaphragm muscle piece, and the output end was connected with the BL-420E+ bio-skill experimental system to record the changes of the rat GG myoelectric and diaphragmatic myoelectricity, each time tracing Record continuously for 4 to 6 hours. The reference electrode is fixed to the left auricle. The recorder has a frequency of 60 Hz and a time constant of 0.3 s. Part of the GG electromyography and diaphragm electromyography will be processed by the EMG integrator.

Step 4: Cerebrospinal fluid 5-HT2A/2C and 5-HIAA detection: Rats have apnea and decreased genioglossus activity. Take brain tissue or spinal cord, add 1ml saline to grind brain tissue or spinal cord, and centrifuge for centrifugation (3000 rpm 10 minutes) . Take the supernatant. The 5-HT2A/2C and 5-HIAA content of the cerebrospinal fluid of the animal is detected by the radioimmunoassay kit using the molecular biological fluorescence receptor detection technology (or the detection method is selected according to the kit requirements).

Step 5: Brain stem immunohistochemical staining detection 5-HT2A/2C:

After confirming the occurrence of apnea, pentobarbital sodium (100 mg/kg) was intravenously anesthetized, thoracic, and the left ventricle was intubated to the ascending aorta saline to flush the blood, then 4% paraformaldehyde phosphate buffer Liquid perfusion, removal of the skull, brain tissue placed in 10% neutral formaldehyde After fixing for 48 hours in the medium, continuous brain slices (sagittal sections) were taken and immunohistochemical staining was performed to detect 5-HT2A/2C.

After the above steps, the animal model of inhibiting the excitability of the nucleus raphe nucleus neurons is used to increase the excitability of the nucleus raphe nucleus, release 5-HT, GG electrical activity and systolic function, and achieve the purpose of dilating the pharyngeal cavity, further for OSA. The patient was treated with high frequency stimulation to treat the disease, providing theoretical and laboratory evidence.

Figure 1 shows the changes in the respiratory motion curve of the insular cortex of rats after electrical stimulation and glutamate stimulation in the nucleus. Figure A. Normal breathing curve of rats. B. Insular cortex Electrical stimulation (arrow), the rats breathe shallowly, then stop for about 2.5 seconds, and after a period of about 10 seconds, the breathing rhythm becomes normal, but the breathing rate is very low. C. Respiratory arrest with L-glutamate-induced island cortex (INSX arrow: 0.3 μL for 23 minutes). D. The nucleus is blocked by lidocaine and then stimulates the island leaves. The animals do not have apnea.

Figure 2 shows the changes in GG myoelectricity in the insular cortex of rats after electrical stimulation of the nucleus. The first curve of each group in the figure is the respiratory motion curve, the middle curve is GG, and the third curve is integral. A. The control group showed no change. Along with the breathing rhythm, GG shows a rhythmic discharge, an increase in the integral of myoelectricity. B. Electrical stimulation of the island leaves produces apnea (indicated by the arrow), GG myoelectrics disappear. C. Lidocaine blocked the nucleus, the apnea disappeared, the rhythm became normal, and GG myoelectric recovery.

The invention will now be described by way of specific examples:

Example 1:

The high-frequency current is used to stimulate the nucleus, and a square wave with a current intensity of 50 uA, a frequency of 130 Hz, and a wave width of 0.3 ms is set for 30 minutes. Example 2:

The high-frequency current is used to excite the nucleus, and a square wave with a current intensity of 50 uA, a frequency of 280 Hz, and a wavelength width of 0.3 ms is set for 30 minutes.

Example 3:

The high frequency current is used to stimulate the helium nucleus, and the square wave with a current intensity of lOOuA, a frequency of 280 Hz, and a wavelength width of 0.3 ms is set for 30 minutes.

Example 4:

The high-frequency current was used to stimulate the lateral nucleus, and a square wave with a current intensity of 150 uA, a frequency of 50 Hz, and a wavelength of 0.3 ms was set for 30 minutes.

Example 5

The high frequency current is used to stimulate the helium nucleus, and a square wave with a current intensity of 150 uA, a frequency of 280 Hz, and a wavelength width of 0.3 ms is set for 30 minutes.

Example 6:

The high frequency current is used to stimulate the helium nucleus, and a square wave with a current intensity of 120 uA, a frequency of 250 Hz, and a wave width of 0.3 ms is set for 30 minutes.

Example 7

The high-frequency current is used to excite the nucleus, and a square wave with a current intensity of 11 OuA, a frequency of 200 Hz, and a wavelength of 0.3 ms is set for 30 minutes.

Example 8

The high-frequency current is used to excite the nucleus, and a square wave with a current intensity of 50 uA, a frequency of 50 Hz, and a wavelength width of 0.3 ms is set for 30 minutes.

Claims

Capsule request

1. High-frequency current in the treatment of P plug-in sleep R apnea syndrome clock application

2. The application of high frequency turbulence according to claim 1 in the treatment of obstructive sleep apnea syndrome, characterized in that high frequency current 剌潋 side entanglement therapy for obstructive sleep apnea synthesis

3. The application of the high frequency current according to claim 1 or 2 in the treatment of obstructive sleep apnea syndrome W, characterized in that: the high frequency current parameter of the building is 5 (W50uA» frequency 50 280 Hz, liquid helium is 0, 3 Brain sinusoidal wave; sputum lateral nucleus smelled for 30 minutes.