Gastroesophageal reflux disease (GERD) is a challenging gastrointestinal disorder, and proton pump inhibitors (PPIs) are typically the first line of treatment. However, up to 40% of GERD patients experience little to no relief or only partial relief of their symptoms after receiving PPI therapy. Among these patients, who do not respond to high-dose PPIs taken twice daily, more than 90% exhibit conditions related to brain-gut axis communication disorders, such as esophageal hypersensitivity and functional heartburn. Visceral hypersensitivity and esophageal hypervigilance are the two key causes of esophageal symptoms in this group of patients. According to the Rome IV consensus on esophageal disorders, five categories are identified: functional chest pain, functional heartburn, globus sensation, functional dysphagia, and esophageal hypersensitivity. The diagnostic criteria state that patients must have chronic esophageal symptoms, and any structural, inflammatory, or motility abnormalities must be excluded. Therefore, diagnosing brain-gut axis communication disorders in the esophagus requires upper gastrointestinal endoscopy, esophageal pH-impedance testing, and high-resolution esophageal manometry. Neuromodulators, which regulate peripheral and central pain sensitivity, are a cornerstone of pharmacological treatment for brain-gut axis communication disorders and associated symptoms. Additionally, growing evidence supports the use of brain-gut axis behavioral therapies, such as gut-directed hypnotherapy and cognitive behavioral therapy (CBT), to effectively treat these disorders. However, research on neuromodulators and CBT in brain-gut axis communication disorders remains limited, and their efficacy is still unclear. The aim of this study is to investigate the effectiveness and role of CBT in treating brain-gut axis communication disorders. The information gained from this research will help clarify the pathophysiological mechanisms related to brain-gut axis communication abnormalities and refractory GERD symptoms. Furthermore, the findings will guide the development of effective treatment strategies for patients with brain-gut axis communication disorders who do not respond to PPI therapy in clinical practice.

All participants will undergo questionnaire assessments and heart rate variability (HRV) measurements prior to treatment. The questionnaires include the Gastroesophageal Reflux Disease Questionnaire (GERDQ), PROMIS GERD, DSI & GSS, RSI, the Brief Esophageal Dysphagia Questionnaire (BEDQ), the Esophageal Hypersensitivity and Anxiety Scale (EHAS), Visceral Sensitivity Index (VSI), Sleep and Psychosocial Questionnaires (Pittsburgh Sleep Quality Index [PSQI], Taiwan Depression Questionnaire [TDQ], State-Trait Anxiety Inventory [STAI], Functional Dyspepsia [FD] Questionnaire, Irritable Bowel Syndrome [IBS] Questionnaire, and Quality of Life Questionnaire [SF-12, Northwestern Esophageal Quality of Life Questionnaire NEQOL]). HRV measurements will be conducted using a non-invasive "MindTech" physiological feedback system (Ministry of Health and Welfare Medical Device License No. 011374).

Afterwards, a single-blind trial with computer-generated random allocation will be conducted. Participants will undergo either six weeks of cognitive behavioral therapy (CBT) led by a therapist or six weeks of lifestyle management (sham control). Each group will receive one session per week, with each session lasting one hour. After six weeks of counseling, participants will undergo another round of questionnaire assessments and HRV measurements at the 12th week of the study. The questionnaire assessment and HRV measurements will take approximately 20 to 30 minutes to complete.

Cognitive behavioral therapy (CBT) will follow these steps in sequence: (1) education and tracking initiation, (2) introduction to heart rate variability and breathing, (3) cognitive restructuring and breathing techniques, (4) cognitive diffusion and behavioral experiments, (5) problem-focused and emotion-focused coping strategies, (6) conclusion of therapy and relapse prevention.

Lifestyle management (sham control) will follow these steps in sequence: (1) education and tracking initiation, (2) dietary habits: what, when, where, why, (3) changing my diet: strategies and obstacles, (4) lifestyle factors: alcohol, smoking, and sugar, (5) lifestyle factors: sleep and exercise, (6) conclusion of therapy and relapse prevention.

In this study, we will use a non-invasive physiological signal sensor connected to the physiological feedback system to measure participants' physiological signals, including electrocardiogram (ECG) and respiration. Prior to measurement, participants will be attached with ECG electrodes for a two-lead ECG, which will be converted into heart rate variability indicators. Additionally, a non-invasive respiratory sensor will measure the participant's breaths per minute. Except for a very small percentage of participants who may experience allergic reactions to ECG electrodes, the likelihood of adverse effects is less than 1%.

Inclusion Criteria:

1. Age between 18 and 75 years, with clear consciousness and willingness to sign the informed consent form.
2. Subjects with chronic esophageal symptoms related to disorders of the brain-gut axis communication (such as heartburn, acid reflux, sensation of a foreign body in the throat, difficulty swallowing, and chest pain or discomfort).

Exclusion Criteria:

1. Esophageal strictures, or history of surgery on the esophagus, gastrointestinal tract, or throat.
2. Structural esophageal diseases (such as diverticula, esophageal rings, etc.), infectious esophagitis, erosive esophagitis, eosinophilic esophagitis.
3. Non-erosive gastroesophageal reflux disease or significant esophageal motility disorders.
4. History of or current diagnosis of malignancies in the esophagus, gastrointestinal tract, or other organs.
5. Significant endocrine or rheumatic immune diseases that may affect gastrointestinal motility.
6. Continuous use of medications that may affect esophageal motility within the past month (such as anticholinergics, opioid-like agents, nitrates, calcium channel blockers, etc.).
7. Use of or currently taking antidepressants, selective serotonin reuptake inhibitors, or other psychotropic medications within the past three months.
8. Pregnant or breastfeeding women.
9. Individuals with mental illness or those who are unable to cooperate.
10. Known allergy to tricyclic antidepressants.
11. Known allergy to selective serotonin reuptake inhibitors.
12. Known allergy to any component of proton pump inhibitors.