In recent years, gastroesophageal reflux disease (GERD) as a benign esophageal disease has attracted more and more attention from doctors and patients. Research on its typical intra-digestive symptoms and traditional treatment modalities has been quite mature, and the focus of research has been mainly on its atypical extra-digestive symptoms and the application of new treatment strategies. In April 2006, academician Wang Zhonghao called on the medical community to re-recognize GERD, and a large number of patients, especially those with respiratory symptoms such as asthma and cough, have been effectively treated.Stretta micro radiofrequency treatment of the lower esophagus has also been applied to the GERD community as a fast, painless and effective treatment. With the increase in the number of patients treated and in-depth follow-up, we have observed that vagus nerve dysfunction may be the main mechanism for the onset and progression of symptoms in some of these patients, which we have tentatively hypothesized to be the vagus nerve dysfunction syndrome (VDS), which is different from the current medical concept of gastroesophageal reflux disease (GERD) in pathogenesis. In terms of pathogenesis, this syndrome is fundamentally different from the various symptoms in the digestive tract and outside the digestive tract caused by GERD, as recognized by the current medical profession. Anatomical basis The tenth pair of cerebral nerves, the vagus nerve, is a mixed nerve with the longest travel and widest distribution in the whole body, and contains four types of fibers: parasympathetic fibers, general visceral sensory fibers, general somatosensory fibers, and special visceral motor fibers. The vagus nerve sends out many branches in the cranial, thoracic and abdominal regions, among which the more important branches are: 1. The superior laryngeal nerve, the outer branch innervates the cricothyroid muscles. The internal branches are distributed to the laryngeal mucosa above the glottic fissure, as well as to the epiglottis and the root of the tongue, etc. 2. The cervicocardiac branch, which has two branches, the upper and lower branches, and the lower branch enters the thoracic cavity to form the cardiac plexus with the sympathetic nerves. 3. The recurrent laryngeal nerve, which innervates all laryngeal muscles except the cricothyroid muscle by its motor fibers, and distributes sensory fibers to the laryngeal mucosa below the glottic fissure. The recurrent laryngeal nerve gives off cardiac, bronchial, and esophageal branches in its course, participating in the cardiac, pulmonary, and esophageal plexuses, respectively.4 The bronchial and esophageal branches, in addition to innervating smooth muscles and glands, also conduct sensations in the organs and pleura.5 The anterior gastric branch and the hepatic branch, which originate from the anterior vagal trunk in the vicinity of the cardia, are located along the antrum of the stomach and the hepatic branch, which originates in the vicinity of the cardia. The anterior gastric branch runs along the curvature of the stomach to the right and sends out 4-6 small branches along the way, which are distributed to the anterior wall of the stomach, and its terminal branch is distributed to the anterior wall of the pylorus in the form of “crow’s paw” branch. The hepatic branch has one to three branches, which participate in the hepatic plexus and distribute in the liver and gallbladder along with the branches of the hepatic innominate artery.6 The postgastric branch originates from the posterior vagal trunk near the cardia, and travels along the deeper part of the gastric lesser curvature, and sends out branches to the posterior wall of the stomach along the way. The terminal branch, like the anterior gastric branch, branches in the shape of a “crow’s paw” and distributes in the pyloric sinus and the posterior wall of the pyloric canal. 7. The abdominal branch, originating from the posterior vagal trunk, travels to the right and forms the abdominal plexus with the sympathetic nerves, and accompanies the abdominal trunk, the superior mesenteric artery and the renal artery, etc. It distributes in most of the abdominal organs such as the gallbladder, the spleen, the small bowel, the cecum, the colon, the transverse colon, the liver, the pancreas, and the kidney. 8. Most of the abdominal organs. Second, the characteristics of gastroesophageal reflux disease symptoms Throughout the gastroesophageal reflux disease digestive tract and digestive tract outside the symptoms, from tinnitus and salivation to panic and shortness of breath, from the reflux of gastric acid caused by GERD with esophageal mucosal damage to the bile reflux caused by the absence of esophageal mucosal damage in NERD, from the small children irritable and crying to the adult anxiety and depression, are related to the effector organs of the vagus nerve branch (the larynx, epiglottis, external auditory canal, the heart, the lungs, the esophagus, stomach, gallbladder, etc.) are involved. Does GERD cause symptoms such as tinnitus, sneezing, runny nose, snoring, hoarseness and wheezing, or are all symptoms, including GERD, the result of vagal dysfunction or dysregulation? Moreover, epidemiologic studies have shown that although GERD is an important factor in the occurrence of extra-gastrointestinal symptoms, there is not enough evidence now to show that acid reflux occurs before various accompanying symptoms [1]. III.IMPLICATIONS FROM CLINICAL DATA Implication 1: Why is GERD difficult to cure? Although it is a benign disease, GERD is a chronic recurrent disease. Our long-term follow-up found that, especially for patients with respiratory tract problems, although acid reflux symptoms such as acid reflux and heartburn have significantly improved or even disappeared after oral acid-suppressing drugs or even gastric fundoplication, the respiratory tract symptoms have not improved significantly or have not improved in the long term. All of these patients were excluded from the presence of allergic asthma and primary asthma, and the use of antispasmodic and asthma medications had little efficacy, and most of them needed to use hormones or wait for the symptoms to disappear on their own. Our explanation is that although acid-suppressing drugs and fundoplication reduce the exposure of the lower esophagus to acid, vagal dysfunction persists or occurs intermittently, resulting in pathological changes in the effector organs of the “sensitive branches” of the vagus nerve. Insight 2: Why are acid reflux and wheezing symptoms mild during the day and pronounced at night? Many patients with respiratory symptoms of wheezing in the description of the symptoms, in particular, emphasized that the nighttime asthma attacks have two characteristics, first, there is a time pattern, basically in the early hours of the morning between points. The second is the severity of the symptoms, with the possibility of life-threatening, and even cases of emergency tracheotomy after laryngospasm and fainting. Our explanation is: because the autonomic nerves in the process of regulating the activities of the body there are adapted to the body’s biological rhythm cycle, and is the role of parasympathetic and sympathetic nerves together. The vagus nerve, as the main parasympathetic nerve, is dysfunctional at night when the body is at rest, and loses its normal tone regulation of the target organs, or its antagonistic sympathetic nervous system fails to play an antagonistic role in a timely manner, resulting in pathological changes in the effector organs of the “sensitive branches”. Inspiration 3: Why there are NERD and non-acidic GERD? NERD refers to non-erosive reflux esophagitis (NERD), which is currently considered as a type of GERD, with symptoms of heartburn, acid reflux, and chest pain due to the reflux of bile into the stomach, but without any breakage of the esophageal mucosa [2]. In patients with typical NERD symptoms, about 20% of 24-h esophageal PH monitoring does not suggest pathologic acid reflux but has a positive symptom index [3]. Non-acidic GERD is defined as reflux of gastric contents into the esophagus that results in only minor changes in esophageal pH or the presence of bile reflux. It has been reported in the literature [4] that the pathophysiologic mechanisms of non-acidic GERD and acidic GERD are not very different, mainly the presence of transient lower esophageal sphincter relaxations (TLESRs), but only the nature of the refluxed material is different. This literature specifically states that non-acidic reflux can also cause both intra- and extra-esophageal symptoms, and although the mechanism is unknown, the relationship between non-acidic reflux and symptom perception and pH is now known [5]. The problem would be very simple if explained by monism, since both the lower esophageal sphincter and the stomach, duodenum, and gallbladder are effector target organs of the vagus nerve, and impaired vagal modulation renders each effector target organ potentially pathologically altered (enhanced digestive function?). . Inspiration #4: Why is there a high incidence of GERD in the pediatric population? Studies have shown that chronic pharyngotracheal diseases are associated with pathologic GERD in at least 59% of pediatric patients [1,6]. In addition to smoking, alcohol consumption, overeating, medications, H. pylori infection, and nightlife-induced dysphoria, we believe that the most plausible explanation is due to the imperfect development of the body’s nervous system during infancy and childhood, which leads to the occurrence of pathologic reflux. CLINICAL EVIDENCE Zhou XX, a female, was admitted to the hospital with reflux for 45 years, chest tightness and pain for 35 years, and intermittent pharyngeal tightness for 8 years. This patient also had significant arrhythmia and ventricular tachycardia. According to the current viewpoint, this is a typical GERD case with extra-esophageal symptoms. After diagnosis of GERD, the patient was treated with micro radiofrequency in the lower esophagus, after which the phenomena of regurgitation, chest tightness and pharyngeal tightness improved significantly, and the arrhythmia and ventricular tachycardia also improved significantly. It is well known that the automatic regulation of cardiac autonomic nerves under normal conditions is balanced by the joint interaction of sympathetic and vagal nerves, and the heart will show various arrhythmias if any external factor disturbs this balance. For this patient, our explanation is that the radiofrequency heat energy applied to the lower esophagus stimulates the esophageal branch of the vagus nerve, which reflexively regulates the cardiac branch of the vagus nerve and the superior laryngeal nerve innervating the heart, so that the regulation of the heart and the laryngeal muscles, which were originally “out of balance”, tends to be balanced. Patient Zhang XX, male, was admitted to the hospital for 4 years with recurrent episodes of stridor. After detailed questioning of the patient’s history, he complained of occasional acid reflux and heartburn, and often suffered from nausea. This patient was treated with micro radiofrequency in the lower esophagus and long-term oral antispasmodic, asthma and acid-suppressing drugs, and the phenomenon of recurrent wheezing still existed. We simultaneously monitored the patient’s 24-hour esophageal PH and ambulatory electrocardiography to understand the patient’s autonomic nervous system function by heart rate variability (HRV). The results showed that the patient’s vagal tone and sympathetic tone were significantly elevated, and more importantly, we found that a slowing of the heart rate occurred simultaneously with the development of acid reflux, as measured by the 24-hour esophageal PH and electrocardiographic variability control. This phenomenon seems to be more indicative of the fact that all initiating factors originate from the vagus nerve. The actions of the sympathetic and parasympathetic nerves on the same organ are both antagonistic and unifying. Normally, when the organism is in a state of quiet or sleep, the activity of the parasympathetic nerves is increased and the sympathetic nerves are inhibited, resulting in a slowing of the heartbeat, a fall in blood pressure, bronchoconstriction (asthma?), a narrowing of the pupils, and a decrease in digestive activity. , pupil constriction, increased digestive activity (acid reflux, reflux of food, bile reflux?) and other phenomena. Either an increase in parasympathetic activity or a decrease in sympathetic activity will disrupt this balance, which in turn will lead to pathological changes. Autonomic influences on GERD have also been reported in previous studies, such as: visceral hypersensitivity, enteric nervous system, vagal-vagal reflexes, brain-gut axis, etc [7]. However, all of them were passed over as part of the nervous system discussed last in the pathogenesis. Regarding the diagnosis and treatment of such patients, HRV is a new tool for noninvasive assessment of autonomic activity and is a commonly used quantitative indicator for independent evaluation of autonomic activity. With the exception of primary asthma, gastric ulcers, esophagitis, and allergic asthma, and with the simultaneous monitoring of the patient’s 24-hour esophageal pH and ambulatory electrocardiography, HRV assessment can screen for abnormal autonomic function, which, when compared with esophageal pH, will aid in the diagnosis of vagal dysfunction syndrome (VDS). Sympathetic and parasympathetic activity is regulated in the higher centers of the brain, particularly in the limbic lobe and hypothalamus. The following vagal treatments have been reported in the literature: oral anticholinergic medications, surface physical therapy stimulation, vagus nerve stimulation, or implantable vagus nerve stimulation generators. However, the effects are limited and are associated with adverse effects: hoarseness in 37%, sore throat in 11%, cough in 7%, shortness of breath in 6%, sensory abnormalities in 6%, and muscle pain in 6%. More recently, it has been suggested that there is also an autonomic nervous system that is more advanced than sympathetic and parasympathetic nerves, a social nervous system unique to mammals [8]. To summarize, the cause of recurrent attacks in some patients with GERD may be due to vagus nerve dysfunction, but currently there is a lack of effective means to regulate the vagus nerve, and the main treatment may need to return to the body’s own regulation.