Esophageal Visceral Hypersensitivity and Hypervigilance in Disorders of Gut-brain Interaction: the Roles of Cognitive-behavioral Therapy
Phase: NA
Conditions: Gut-Brain Disorders, GERD Without Erosive Esophagitis
Sponsor: Hualien Tzu Chi General Hospital

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               1 
 
Hualien Tzu Chi Hospital                        
The Application for In-Hospital Medical Technology Research Project 
1.Basic Information                      Application Number：________________ 
Project Category 
(Select one) 
■Individual Research Project: The project leader is a senior staff member of the 
hospital. 
■Experimental Research (Up to 800,000 NTD   
□Non-Experimental Research (Up to 400,000 NTD) 
□Holistic Care Departmental Project (Up to 800,000 NTD) (Only department heads 
are eligible to apply) 
□New Staff Research Project (Up to 200,000 NTD) 
□University-Hospital Collaborative Research Project (Up to 400,000 NTD) 
□Ministry of Science and Technology Transfer to Hospital Project (Up to 800,000 
NTD) 
□Medical Education Research Project (Up to 400,000 NTD) 
Personnel Category 
(Select one) 
■Physician 
  □Non-Physician 
Project Title 
Esophageal visceral hypersensitivity and hypervigilance in disorders of gut-brain 
interaction: the roles of cognitive-behavioral therapy 
Name of the Project 
Leader 
Wei-Yi Lei 
Title/Position Attending 
Physician 
Applying 
Department/Division 
Gastroenterology 
Department 
Project Execution 
Period 
From January 1, 2024 to December 31, 2025  
Research Nature 
and Classification 
□Basic Research ■Applied Research   □Technology Development 
(Note: Those who select Applied Research and Technology Development must also 
select the category of Innovation R&D.) 
Innovation R&D Classification：■(1) Clinical Research          
□(2) Translational Research □(3) Medical Engineering and Materials 
□(4) Informatio □(5) Medical Assistance Operations □(6) Others, please specify 
______________。 
Holistic Care 
(Please refer to the 
term description, 
multiple selections 
are allowed) 
Holistic Care Classification： 
(1) Patient-Centered (■ Physical, □ Psychological, ■ Environmental, □ Spiritual) 
(2) Health Education (□ Behavior Change, ■ Health Promotion, ■ Disease 
Prevention, ■ Early Diagnosis, □ Early Treatment) 
(3) Others, please specify ______________________________________________。 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               2 
Has this in-house project applied for the 2023 Ministry of Science and Technology's Special Research 
Program? 
■ No □ Yes. 
Has any government agency subsidy for research projects been applied for this year? 
□ No ■ Yes, a total of 1   projects. 
A total of 1   in-house research projects have been applied for this year as the principal investigator 
(jointly hosted projects are not included). 
The priority of this project is 1  . 
Has this project applied for: 
□ No need 
■ Human Experiments / Human Samples (including human embryos/human embryonic stem cells) 
□ Animal Experiments 
□ Biosafety (including recombinant DNA experiments/genetically modified organism field trials/Level 2 or 
higher infectious biological materials) 
【Please check the applicable items】 
Project Contact 
Person 
Name: Lei Wei-Yi 
Phone: (Office) (03) 8561825-13224  (Home) 0970-339629 
E-Mail: aquarious@seed.net.tw 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               3 
2. Application for Subsidy Funding (The budget allocation will be included in the 
review and evaluation criteria, please do not inflate the figures.) 
Based on the actual needs of the research project, the following items can be applied for subsidy 
funding: 
• 
For individual research projects:  
o Experimental research: Maximum of 800,000 NTD 
o Non-experimental research: Maximum of 400,000 NTD 
• 
For new personnel research projects: The total research funding is limited to 200,000 NTD. 
• 
For collaborative research projects between schools and institutions: The total research 
funding is limited to 400,000 NTD. 
• 
For holistic care department projects: The maximum funding is 800,000 NTD. 
• 
For Ministry of Science and Technology transferred in-house projects: The maximum 
funding is 800,000 NTD. 
Subsidy Items 
Requested Amount 
Administrative 
Expenses 
1. Research 
Personnel Costs 
480,000 NTD 
2. Experimental 
Animal Costs 
0 NTD 
3. Consumables, 
Materials, Books, 
and Miscellaneous 
Expenses 
160,000 NTD 
Research Equipment Costs 
0 NTD 
Total Amount 
640,000 NTD 
 
3. Equipment Configuration 
The names of the main instruments required for this project, their placement locations, and the 
signature of the responsible person consenting to their use. 
Instrument Name 
Installation Location 
(Department) 
Signature and Seal of the 
Department Head Approving the Use 
of the Instrument 
 
 
 
 
 
 
 
 
 
 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               4 
4. Personnel Involved in the Project 
(1) Principal Research Personnel 
Category 
(Principal 
Investigator,  
Co-Principal 
Investigator, 
Collaborating 
Principal 
Investigator, 
Research 
Assistant, etc.) 
Name 
Current Position 
Specific Job Role, Tasks, and Scope of Work in this 
Research Project 
Principal 
Investigator Lei Wei-Yi 
Attending Physician, 
Gastroenterology 
Research project planning and participant 
recruitment, progress monitoring, data statistical 
analysis, and report writing. 
Co-Principal 
Investigator 
Chen Jian-
Lin 
Director of Gastroenterology 
Department 
Project progress supervision, project planning 
discussions, participant recruitment, and data 
analysis. 
Co-Principal 
Investigator 
Weng Ming-
Wen 
Attending Physician, 
Gastroenterology 
Research project participant recruitment and actual 
case handling. 
Co-Principal 
Investigator Yi Zhi-Xun 
Attending Physician, 
Gastroenterology 
Research project participant recruitment and actual 
case handling. 
Co-Principal 
Investigator Liu Zuo-Cai Director of the Digestive 
Function Testing Department 
Research project participant recruitment and actual 
case handling. 
Co-Principal 
Investigator 
Hong Rui-
Sheng 
Attending Physician, 
Gastroenterology 
Research project participant recruitment and actual 
case handling. 
Co-Principal 
Investigator 
Wang Jun-
Wei 
Attending Physician, 
Gastroenterology Department, 
Kaohsiung Medical University 
Hospital 
Research project participant recruitment and actual 
case handling. 
Co-Principal 
Investigator 
Liang Shu-
Wei 
Attending Physician, 
Gastroenterology Department, 
Chung Shan Medical 
University Hospital 
Research project participant recruitment and actual 
case handling. 
Co-Principal 
Investigator 
Wang Wen-
Hui 
Director of Gastroenterology 
Department, E-Da Hospital 
Research project participant recruitment and actual 
case handling. 
Co-Principal 
Investigator 
Hsieh Ming-
Tsung 
Attending Physician, 
Gastroenterology Department, 
National Cheng Kung 
University Hospital 
Research project participant recruitment and actual 
case handling. 
Co-Principal 
Investigator Lin Yi-Mei 
Professor, Department of 
Psychology, Kaohsiung 
Medical University 
Cognitive Behavioral Therapy coordination and 
data analysis. 
Co-Principal 
Investigator Lin Hui-Min 
Dietitian, Clinical Nutrition 
Division, Department of 
Nutrition 
Developing nutrition education materials and 
arranging the nutrition consultation process. 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               5 
Research 
Personnel 
Lin Pei-Yun Psychotherapist, Yuli Hospital Conducting Cognitive Behavioral Therapy. 
Research 
Personnel 
Hsu Ssu-Ting 
Counseling Psychologist, 
Secret Garden Counseling 
Center 
Conducting Cognitive Behavioral Therapy. 
Research 
Personnel 
Su Zhen-
Ying 
Dietitian, Clinical Nutrition 
Division, Department of 
Nutrition 
Conducting nutrition counseling and education. 
Research 
Assistant 
Huang Chun-
Hsiang 
Research Assistant 
Survey administration, data collection, organization 
and analysis, and handling administrative tasks. 
※If there are insufficient fields, please copy them as needed. 
 
(2) Research projects that the principal investigator, co-principal investigator, and co-
researchers have participated in during the past three years. 
Name 
Project Name 
Role and 
Responsibilities in the 
Project 
Start and 
End Date 
Funding 
Agency 
Lei Wei-
Yi 
Exploring the roles and interrelationships of 
esophageal hypersensitivity, psychological 
distress, and functional gastrointestinal disorders 
in the pathophysiological mechanisms of 
esophageal symptoms in patients. 
Principal Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
Exploring the pathophysiological mechanisms and 
treatment strategies of gastroesophageal reflux 
disease (GERD) through the distribution of 
afferent nerves, esophageal motility, and 
pharmacological regulation. 
Principal Investigator 
2022/8/1~ 
2025/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Lei Wei-
Yi 
Exploring the effects of opioid analgesics on the 
pathophysiological mechanisms of esophageal 
contraction and reflux characteristics, as well as 
their clinical applications. 
Principal Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
The efficacy of Jingsi Herbal Concentrate on long 
COVID symptoms—gut-brain axis dysregulation 
and related physical and mental symptoms: A 
randomized double-blind clinical trial. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Tzu Chi 
Medical 
Foundation 
Lei Wei-
Yi 
Exploring the interaction between upper gastric 
belching, physical and mental symptoms, and 
esophageal acid reflux: Clinical applications for 
optimizing the treatment of gastroesophageal 
reflux disease (GERD). 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
Using high-resolution pharyngeal function testing 
to analyze the pharyngeal swallowing physiology 
and dynamics in patients with ineffective 
esophageal motility. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
Exploring the efficacy and physiological changes 
of anti-reflux mucosal ablation in proton pump 
inhibitor (PPI)-dependent gastroesophageal reflux 
disease (GERD). 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               6 
Lei Wei-
Yi 
Exploring the sensitivity to capsaicin, motility 
sensation function, and the physiological features 
of reflux in the esophagus: Clinical impact and 
treatment guidelines for esophageal dysfunction 
and gastroesophageal reflux disease (GERD). 
Co-Principal 
Investigator 
2023/8/1~ 
2026/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Lei Wei-
Yi 
Exploring the pathophysiological mechanisms of 
gastroesophageal reflux disease (GERD) through 
esophageal reflux clearance capacity, mucosal 
integrity, and psychosocial characteristics, and 
establishing a basis for precise diagnosis and 
treatment. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
The application of high-resolution impedance 
pharyngeal function testing and the Sydney 
Swallowing Questionnaire in oropharyngeal 
dysphagia and voice disorders. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
The application of artificial intelligence in high-
resolution esophageal function testing: A study on 
unsupervised computational models based on deep 
learning. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
Application of supervised learning artificial 
intelligence in analyzing 24-hour esophageal pH-
impedance monitoring: Technological efficacy and 
clinical 
applications 
in 
diagnosing 
gastroesophageal reflux disease (GERD). 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
Exploring the clinical characteristics and the 
impact of gut microbiota in patients with 
metabolic-associated fatty liver disease under 
dietary and exercise regulation. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
The efficacy of Jingsi Herbal Drink on the 
physical and mental symptoms of functional 
dyspepsia: A randomized double-blind clinical 
trial. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Tzu Chi 
Medical 
Foundation 
Lei Wei-
Yi 
Exploring the pathophysiological role of 
esophageal mucosal afferent nerve distribution in 
gastroesophageal reflux disease (GERD) with 
concurrent esophageal motility dysfunction. 
Principal Investigator 
2020/8/1~ 
2022/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Lei Wei-
Yi 
Exploring the pathophysiological impact of 
esophageal contraction, mucosal integrity, and 
acid sensitivity on gastroesophageal reflux disease 
(GERD) and the basis for treatment strategies. 
Co-Principal 
Investigator 
2020/8/1~ 
2023/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Lei Wei-
Yi 
Exploring the role of esophageal microbiota in 
gastroesophageal reflux disease (GERD) through 
novel impedance parameters, clinical subtypes, 
and hypersensitivity. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
Exploring the interrelationship and pathogenic 
mechanisms of esophageal acid sensitivity, 
secondary esophageal contractions, and subtypes 
of gastroesophageal reflux disease (GERD). 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Lei Wei-
Yi 
Exploring the clinical application of high-
resolution impedance pharyngeal function testing 
in oropharyngeal dysphagia and drug response. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin The efficacy of Jingsi Herbal Concentrate on long 
COVID symptoms—gut-brain axis dysregulation 
Principal Investigator 
2023/01/01~ 
2023/12/31 
Tzu Chi 
Medical 
Foundation 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               7 
and related physical and mental symptoms: A 
randomized double-blind clinical trial. 
Chen 
Jian-Lin 
Exploring the interaction between upper gastric 
belching, physical and mental symptoms, and 
esophageal acid reflux: Clinical applications for 
optimizing the treatment of gastroesophageal 
reflux disease (GERD). 
Principal Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Exploring the relationship between esophageal 
capsaicin sensitivity, motility sensation function, 
and the physiological characteristics of reflux: 
Clinical impacts and treatment guidelines for 
esophageal dysfunction and gastroesophageal 
reflux disease (GERD). 
Principal Investigator 
2023/8/1~ 
2026/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Chen 
Jian-Lin 
The efficacy of Jingsi Herbal Drink on the physical 
and mental symptoms of functional dyspepsia: A 
randomized double-blind clinical trial. 
Principal Investigator 
2022/1/1~ 
2022/12/31 
Tzu Chi 
Medical 
Foundation 
Chen 
Jian-Lin 
Exploring the pathophysiological mechanisms of 
gastroesophageal reflux disease (GERD) through 
esophageal reflux clearance capacity, mucosal 
integrity, and psychosocial characteristics, and 
establishing a basis for precise diagnosis and 
treatment. 
Principal Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Exploring the pathophysiological mechanisms and 
interrelationships of esophageal hypersensitivity, 
psychological distress, and functional 
gastrointestinal disorders in patients with 
esophageal symptoms. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Exploring the efficacy and physiological changes 
of anti-reflux mucosal ablation in proton pump 
inhibitor (PPI)-dependent gastroesophageal reflux 
disease (GERD). 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Using high-resolution pharyngeal function testing 
to analyze the pharyngeal swallowing physiology 
and 
dynamics 
in 
patients 
with 
ineffective 
esophageal motility. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Exploring the pathophysiological mechanisms of 
laryngopharyngeal reflux: Clinical applications of 
artificial intelligence-assisted, precision 
diagnostics, and personalized treatment strategies. 
Co-Principal 
Investigator 
2022/8/1~ 
2025/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Chen 
Jian-Lin 
Exploring the pathophysiological mechanisms and 
treatment strategies of gastroesophageal reflux 
disease (GERD) through the distribution of 
afferent nerves, esophageal motility, and 
pharmacological regulation. 
Co-Principal 
Investigator 
2022/8/1~ 
2025/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Chen 
Jian-Lin 
Exploring the effects of opioid analgesics on the 
pathophysiological mechanisms of esophageal 
contraction and reflux characteristics, as well as 
their clinical applications. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Application of supervised learning artificial 
intelligence in analyzing 24-hour esophageal pH-
impedance monitoring: Technological efficacy and 
clinical 
applications 
in 
diagnosing 
gastroesophageal reflux disease (GERD). 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               8 
Chen 
Jian-Lin 
The application of high-resolution impedance 
pharyngeal function testing and the Sydney 
Swallowing 
Questionnaire 
in 
oropharyngeal 
dysphagia and voice disorders. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
The application of artificial intelligence in high-
resolution esophageal function testing: A study on 
unsupervised computational models based on deep 
learning. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Exploring the clinical characteristics and the impact 
of gut microbiota in patients with metabolic-
associated fatty liver disease under dietary and 
exercise regulation. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Exploring the role of esophageal microbiota in 
gastroesophageal reflux disease (GERD) through 
novel impedance parameters, clinical subtypes, and 
hypersensitivity. 
Principal Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Exploring the interrelationship and pathogenic 
mechanisms of esophageal acid sensitivity, 
secondary esophageal contractions, and subtypes 
of gastroesophageal reflux disease (GERD). 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Exploring the clinical application of high-
resolution impedance pharyngeal function testing 
in oropharyngeal dysphagia and drug response. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Chen 
Jian-Lin 
Exploring 
the 
pathophysiological 
role 
of 
esophageal mucosal afferent nerve distribution in 
gastroesophageal reflux disease (GERD) with 
concurrent esophageal motility dysfunction. 
Co-Principal 
Investigator 
2020/8/1~ 
2022/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Chen 
Jian-Lin 
Improving the diagnosis of laryngopharyngeal 
reflux through the proximal esophageal nighttime 
average baseline mucosal impedance values and 
establishing the indications for proton pump 
inhibitor therapy. 
Co-Principal 
Investigator 
2020/8/1~ 
2022/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Chen 
Jian-Lin 
Exploring the pathophysiological impacts of 
esophageal contraction, mucosal integrity, and acid 
sensitivity on gastroesophageal reflux disease 
(GERD), and establishing treatment strategies 
based on these factors. 
Principal Investigator 
2020/8/1~ 
2023/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Weng 
Ming-
Wen 
Exploring the efficacy and physiological changes 
of anti-reflux mucosal ablation in proton pump 
inhibitor (PPI)-dependent gastroesophageal reflux 
disease (GERD). 
Principal Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Weng 
Ming-
Wen 
Exploring the pathophysiological mechanisms of 
laryngopharyngeal reflux: Clinical applications of 
artificial intelligence-assisted precision diagnostics 
and personalized treatment strategies. 
Principal Investigator 
2022/8/1~ 
2025/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Weng 
Ming-
Wen 
Using supervised learning artificial intelligence to 
analyze 24-hour esophageal pH-impedance 
monitoring: Technological efficacy and clinical 
applications in the diagnosis of gastroesophageal 
reflux disease (GERD). 
Principal Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Weng 
Ming-
Wen 
The therapeutic effects of concentrated Jingsu 
herbal drink on physical and psychological 
symptoms 
of 
long 
COVID—gut-brain 
axis 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Tzu Chi 
Medical 
Foundation 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               9 
dysregulation: A randomized double-blind clinical 
trial. 
Weng 
Ming-
Wen 
Exploring 
the 
interplay 
between 
belching, 
psychological symptoms, and esophageal acid 
reflux: Clinical applications for optimizing the 
treatment of gastroesophageal reflux disease 
(GERD). 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Weng 
Ming-
Wen 
Exploring the pathophysiological role and interplay 
of esophageal hypersensitivity, psychological 
distress, and functional gastrointestinal disorders in 
patients with esophageal symptoms. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Weng 
Ming-
Wen 
Analyzing the pharyngeal swallowing physiology 
in patients with ineffective esophageal motility 
using high-resolution pharyngeal function testing. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Weng 
Ming-
Wen 
Exploring the relationship between esophageal 
capsaicin sensitivity, motility sensation, and 
physiological features of reflux: Clinical impacts 
and treatment guidelines for esophageal 
dysfunction and gastroesophageal reflux disease 
(GERD). 
Co-Principal 
Investigator 
2023/8/1~ 
2026/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Weng 
Ming-
Wen 
The application of high-resolution impedance 
pharyngeal function testing and the Sydney 
Swallowing Questionnaire in the assessment of 
oropharyngeal swallowing difficulties and voice 
disorders. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Weng 
Ming-
Wen 
The application of artificial intelligence in high-
resolution esophageal function testing: A study 
using 
an 
unsupervised 
deep 
learning-based 
algorithm model. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Weng 
Ming-
Wen 
Exploring the clinical characteristics and the impact 
of gut microbiota in patients with metabolic-
associated fatty liver disease under dietary and 
exercise regulation. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Weng 
Ming-
Wen 
The therapeutic effects of Jing Si Herbal Drink on 
the 
psychosomatic 
symptoms 
of 
functional 
dyspepsia: A randomized double-blind clinical 
trial. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Tzu Chi 
Medical 
Foundation 
Weng 
Ming-
Wen 
The use of proximal esophageal nocturnal average 
baseline mucosal impedance values to improve the 
diagnosis of laryngopharyngeal reflux disease and 
establish indications for proton pump inhibitors. 
Principal Investigator 
2020/8/1~ 
2022/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Weng 
Ming-
Wen 
The exploration of the pathophysiological impact 
of esophageal contraction, mucosal integrity, and 
acid sensitivity on gastroesophageal reflux 
disease, along with therapeutic strategies based on 
these factors. 
Co-Principal 
Investigator 
2020/8/1~ 
2023/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Weng 
Ming-
Wen 
Exploring the role of esophageal microbiota in 
gastroesophageal reflux disease through novel 
impedance parameters, clinical classification, and 
hypersensitivity. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Weng 
Ming-
Wen 
Exploring the relationship and pathophysiological 
mechanisms between esophageal acid sensitivity, 
secondary esophageal contraction, and subtypes of 
gastroesophageal reflux disease. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 

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E6A0021096-10                                                                               10 
Weng 
Ming-
Wen 
Exploring the clinical application of high-
resolution 
impedance 
pharyngoesophageal 
function testing in the assessment of pharyngeal 
dysphagia and drug responses. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
The 
efficacy 
of 
Jing's 
Herbal 
Decoction 
Concentrate in treating long COVID symptoms—
gut-brain axis dysfunction and associated physical 
and mental symptoms: A randomized double-blind 
clinical trial. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Tzu Chi 
Medical 
Foundation 
Yi Zhi-
Xun 
Exploring the interaction between belching, 
physical and mental symptoms, and esophageal 
acid reflux: Clinical applications for optimizing 
gastroesophageal reflux disease treatment. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
Exploring the pathophysiological mechanisms and 
interactions 
of 
esophageal 
hypersensitivity, 
psychological 
distress, 
and 
functional 
gastrointestinal 
disorders 
in 
patients 
with 
esophageal symptoms. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
Exploring the efficacy and physiological changes 
of anti-reflux mucosal ablation therapy in proton 
pump inhibitor-dependent gastroesophageal reflux 
disease. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
Analyzing the pharyngeal swallowing physiology 
and 
dynamics 
in 
patients 
with 
ineffective 
esophageal 
motility 
using 
high-resolution 
pharyngoesophageal function testing. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
Exploring the relationship between esophageal 
capsaicin sensitivity, motility sensory function, and 
the 
reflux 
characteristics 
of 
physical 
and 
psychological physiology: Clinical impact and 
treatment guidelines for esophageal dysfunction 
and gastroesophageal reflux disease. 
Co-Principal 
Investigator 
2023/8/1~ 
2026/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Yi Zhi-
Xun 
Exploring the pathophysiological mechanisms of 
gastroesophageal 
reflux 
disease 
through 
esophageal clearance ability, mucosal integrity, and 
psychological characteristics, and establishing the 
basis for precise diagnosis and treatment. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
Exploring the impact of opioid analgesics on the 
pathophysiological mechanisms of esophageal 
contraction and reflux characteristics, and their 
clinical applications. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
The application of high-resolution impedance 
pharyngoesophageal function testing and the 
Sydney Swallow Questionnaire in oropharyngeal 
dysphagia and voice disorders. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
The Application of Artificial Intelligence in High-
Resolution Esophageal Function Testing: A Study 
on Unsupervised Computational Models Based on 
Deep Learning. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
Artificial 
Intelligence 
Analysis 
of 
24-Hour 
Esophageal 
pH 
Impedance 
Testing 
Using 
Supervised Learning: Technical Performance and 
Clinical 
Applications 
in 
the 
Diagnosis 
of 
Gastroesophageal Reflux Disease. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               11 
Yi Zhi-
Xun 
Exploring the Impact of Diet and Exercise 
Regulation 
on 
Clinical 
Features 
and 
Gut 
Microbiota in Patients with Metabolism-Related 
Fatty Liver Disease. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
The Therapeutic Effect of Jinseng Herbal Drink on 
Psychosomatic 
Symptoms 
in 
Functional 
Dyspepsia: A Randomized Double-Blind Clinical 
Trial. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Tzu Chi 
Medical 
Foundation 
Yi Zhi-
Xun 
Exploring the Interrelationship and Pathogenic 
Mechanisms Between Esophageal Acid Sensitivity, 
Esophageal Secondary Contractions, and Subtypes 
of Gastroesophageal Reflux Disease. 
Principal Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
Exploring the Role of Esophageal Microbiota in 
Gastroesophageal Reflux Disease: Its Impact on 
Novel 
Impedance 
Parameters, 
Clinical 
Classification, and Hypersensitivity. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
Clinical 
Application 
of 
High-Resolution 
Impedance Pharyngeal Function Testing in the 
Assessment of Pharyngeal Dysphagia and Drug 
Response. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Yi Zhi-
Xun 
Exploring the Pathophysiological Impact of 
Esophageal Contractions, Mucosal Integrity, and 
Acid Sensitivity on Gastroesophageal Reflux 
Disease and the Basis for Therapeutic Strategies. 
Co-Principal 
Investigator 
2020/8/1~ 
2023/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Liu Zuo-
Cai 
Exploring the Impact of Diet and Exercise 
Regulation 
on 
Clinical 
Features 
and 
Gut 
Microbiota in Patients with Metabolism-Related 
Fatty Liver Disease. 
Principal Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
The Therapeutic Effect of Jinseng Herbal Extract 
on Long COVID Symptoms: Psychosomatic 
Symptoms 
Related 
to 
Gut-Brain 
Axis 
Dysregulation – A Randomized Double-Blind 
Clinical Trial. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Tzu Chi 
Medical 
Foundation 
Liu Zuo-
Cai 
Exploring the Interrelationship Between Belching, 
Psychosomatic Symptoms, and Esophageal Acid 
Reflux: Clinical Applications for Optimizing 
Gastroesophageal Reflux Disease Treatment. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
Exploring the Pathophysiological Mechanisms and 
Interrelationship 
Between 
Esophageal 
Hypersensitivity, Psychological Distress, and 
Functional Gastrointestinal Disorders in Patients 
with Esophageal Symptoms. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
Analyzing 
the 
Pharyngeal 
Physiology 
and 
Dynamics of Swallowing in Esophageal Ineffective 
Peristalsis 
Patients 
Using 
High-Resolution 
Pharyngeal Function Testing. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
Exploring the Efficacy and Physiological Changes 
of Anti-Reflux Mucosal Ablation in Proton Pump 
Inhibitor-Dependent 
Gastroesophageal 
Reflux 
Disease. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
Exploring 
Esophageal 
Capsaicin 
Sensitivity, 
Peristaltic 
Sensory 
Function, 
and 
Psychophysiological 
Reflux 
Characteristics: 
Clinical Impact and Treatment Guidelines for 
Co-Principal 
Investigator 
2023/8/1~ 
2026/07/31 
Ministry of 
Science and 
Technology 
(MOST) 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               12 
Esophageal Dysfunction and Gastroesophageal 
Reflux Disease. 
Liu Zuo-
Cai 
Exploring the Pathophysiological Mechanisms of 
Gastroesophageal 
Reflux 
Disease 
Through 
Esophageal Reflux Clearance Ability, Mucosal 
Integrity, and Psychosocial Traits: Establishing the 
Basis for Precise Diagnosis and Treatment. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
Exploring the Impact of Opioid Analgesics on 
Esophageal 
Contraction 
and 
Reflux 
Characteristics: Pathophysiological Mechanisms 
and Clinical Applications. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
The Application of High-Resolution Impedance 
Pharyngeal Function Testing and the Sydney 
Swallowing 
Questionnaire 
in 
Oropharyngeal 
Dysphagia and Voice Disorders. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
Artificial 
Intelligence 
Analysis 
of 
24-Hour 
Esophageal pH-Impedance Monitoring Using 
Supervised Learning: Technical Performance and 
Clinical 
Applications 
in 
the 
Diagnosis 
of 
Gastroesophageal Reflux Disease. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
The Application of Artificial Intelligence in High-
Resolution Esophageal Function Testing: A Study 
on Unsupervised Computational Models Based on 
Deep Learning. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
The Therapeutic Effect of Jinseng Herbal Drink on 
Psychosomatic 
Symptoms 
in 
Functional 
Dyspepsia: A Randomized Double-Blind Clinical 
Trial. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Tzu Chi 
Medical 
Foundation 
Liu Zuo-
Cai 
Exploring the Role of Esophageal Microbiota in 
Gastroesophageal Reflux Disease: Its Impact on 
Novel 
Impedance 
Parameters, 
Clinical 
Classification, and Hypersensitivity. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
Exploring the Interrelationship and Pathogenic 
Mechanisms Between Esophageal Acid Sensitivity, 
Esophageal Secondary Contractions, and Subtypes 
of Gastroesophageal Reflux Disease. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
Clinical 
Application 
of 
High-Resolution 
Impedance Pharyngeal Function Testing in the 
Assessment of Pharyngeal Dysphagia and Drug 
Response. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Liu Zuo-
Cai 
Exploring the Pathophysiological Impact of 
Esophageal Contractions, Mucosal Integrity, and 
Acid Sensitivity on Gastroesophageal Reflux 
Disease and the Basis for Therapeutic Strategies. 
Co-Principal 
Investigator 
2020/8/1~ 
2023/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Hong 
Rui-
Sheng 
Analyzing 
the 
Pharyngeal 
Physiology 
and 
Dynamics of Swallowing in Esophageal Ineffective 
Peristalsis 
Patients 
Using 
High-Resolution 
Pharyngeal Function Testing. 
Principal Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
The Application of High-Resolution Impedance 
Pharyngeal Function Testing and the Sydney 
Swallowing 
Questionnaire 
in 
Oropharyngeal 
Dysphagia and Voice Disorders. 
Principal Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               13 
Hong 
Rui-
Sheng 
The Therapeutic Effect of Jinseng Herbal Extract 
on Long COVID Symptoms: Psychosomatic 
Symptoms 
Related 
to 
Gut-Brain 
Axis 
Dysregulation – A Randomized Double-Blind 
Clinical Trial. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Tzu Chi 
Medical 
Foundation 
Hong 
Rui-
Sheng 
Exploring the Interrelationship Between Belching, 
Psychosomatic Symptoms, and Esophageal Acid 
Reflux: Clinical Applications for Optimizing 
Gastroesophageal Reflux Disease Treatment. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
Exploring the Pathophysiological Mechanisms and 
Interrelationship 
Between 
Esophageal 
Hypersensitivity, Psychological Distress, and 
Functional Gastrointestinal Disorders in Patients 
with Esophageal Symptoms. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
Exploring the Efficacy and Physiological Changes 
of Anti-Reflux Mucosal Ablation in Proton Pump 
Inhibitor-Dependent 
Gastroesophageal 
Reflux 
Disease. 
Co-Principal 
Investigator 
2023/01/01~ 
2023/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
Exploring 
Esophageal 
Capsaicin 
Sensitivity, 
Peristaltic 
Sensory 
Function, 
and 
Psychophysiological 
Reflux 
Characteristics: 
Clinical Impact and Treatment Guidelines for 
Esophageal Dysfunction and Gastroesophageal 
Reflux Disease. 
Co-Principal 
Investigator 
2023/8/1~ 
2026/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Hong 
Rui-
Sheng 
Exploring the Pathophysiological Mechanisms of 
Gastroesophageal 
Reflux 
Disease 
Through 
Esophageal Reflux Clearance Ability, Mucosal 
Integrity, and Psychosocial Traits: Establishing the 
Basis for Precision Diagnosis and Treatment. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
Exploring the Impact of Opioid Analgesics on 
Esophageal 
Contraction 
and 
Reflux 
Characteristics: Pathophysiological Mechanisms 
and Clinical Applications. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
Artificial 
Intelligence 
Analysis 
of 
24-Hour 
Esophageal pH-Impedance Monitoring Using 
Supervised Learning: Technical Performance and 
Clinical 
Applications 
in 
the 
Diagnosis 
of 
Gastroesophageal Reflux Disease. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
The Application of Artificial Intelligence in High-
Resolution Esophageal Function Testing: A Study 
on Unsupervised Computational Models Based on 
Deep Learning. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
Exploring the Impact of Diet and Exercise 
Regulation 
on 
Clinical 
Features 
and 
Gut 
Microbiota in Patients with Metabolism-Related 
Fatty Liver Disease. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
The Therapeutic Effect of Jinseng Herbal Drink on 
Psychosomatic 
Symptoms 
in 
Functional 
Dyspepsia: A Randomized Double-Blind Clinical 
Trial. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Tzu Chi 
Medical 
Foundation 
Hong 
Rui-
Sheng 
Clinical 
Application 
of 
High-Resolution 
Impedance Pharyngeal Function Testing in the 
Assessment of Oropharyngeal Dysphagia and Drug 
Response. 
Principal Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               14 
Hong 
Rui-
Sheng 
Exploring the Role of Esophageal Microbiota in 
Gastroesophageal Reflux Disease: Its Impact on 
Novel 
Impedance 
Parameters, 
Clinical 
Classification, and Hypersensitivity. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
Exploring the Interrelationship and Pathogenic 
Mechanisms Between Esophageal Acid Sensitivity, 
Esophageal Secondary Contractions, and Subtypes 
of Gastroesophageal Reflux Disease. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Hong 
Rui-
Sheng 
Exploring the Pathophysiological Impact of 
Esophageal Contractions, Mucosal Integrity, and 
Acid Sensitivity on Gastroesophageal Reflux 
Disease and the Basis for Therapeutic Strategies. 
Co-Principal 
Investigator 
2020/8/1~ 
2023/07/31 
Ministry of 
Science and 
Technology 
(MOST) 
Liang 
Shu-Wei 
The Application of Artificial Intelligence in High-
Resolution Esophageal Function Testing: A Study 
on Unsupervised Computational Models Based on 
Deep Learning. 
Principal Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liang 
Shu-Wei 
Artificial 
Intelligence 
Analysis 
of 
24-Hour 
Esophageal pH-Impedance Monitoring Using 
Supervised Learning: Technical Performance and 
Clinical 
Applications 
in 
the 
Diagnosis 
of 
Gastroesophageal Reflux Disease. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liang 
Shu-Wei 
Exploring the Pathophysiological Mechanisms of 
Gastroesophageal 
Reflux 
Disease 
Through 
Esophageal Reflux Clearance Ability, Mucosal 
Integrity, and Psychosocial Traits: Establishing the 
Basis for Precision Diagnosis and Treatment. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liang 
Shu-Wei 
Exploring the Impact of Opioid Analgesics on 
Esophageal 
Contraction 
and 
Reflux 
Characteristics: Pathophysiological Mechanisms 
and Clinical Applications. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liang 
Shu-Wei 
Exploring the Impact of Diet and Exercise 
Regulation 
on 
Clinical 
Features 
and 
Gut 
Microbiota in Patients with Metabolism-Related 
Fatty Liver Disease. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Hualien Tzu 
Chi Hospital 
Liang 
Shu-Wei 
The Therapeutic Effect of Jinseng Herbal Drink on 
Psychosomatic 
Symptoms 
in 
Functional 
Dyspepsia: A Randomized Double-Blind Clinical 
Trial. 
Co-Principal 
Investigator 
2022/1/1~ 
2022/12/31 
Tzu Chi 
Medical 
Foundation 
Liang 
Shu-Wei 
Exploring the Role of Esophageal Microbiota in 
Gastroesophageal Reflux Disease: Its Impact on 
Novel 
Impedance 
Parameters, 
Clinical 
Classification, and Hypersensitivity. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Liang 
Shu-Wei 
Exploring the Interrelationship and Pathogenic 
Mechanisms Between Esophageal Acid Sensitivity, 
Esophageal Secondary Contractions, and Subtypes 
of Gastroesophageal Reflux Disease. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
Liang 
Shu-Wei 
Clinical 
Application 
of 
High-Resolution 
Impedance Pharyngeal Function Testing in the 
Assessment of Oropharyngeal Dysphagia and Drug 
Response. 
Co-Principal 
Investigator 
2021/1/1~ 
2021/12/31 
Hualien Tzu 
Chi Hospital 
※If there are insufficient fields, please copy them as needed. 
 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               15 
5. Research Related to Costs 
Project Name 
Description 
Unit Price 
(NTW) 
Quantity 
Total Price 
(NTW) 
Remarks 
1. Operational Expenses 
1.Research 
Personnel Costs 
(For related 
insurance 
premiums, please 
consult the 
Human 
Resources 
Department) 
(1) Full-time Personnel (for 
individual project 
applications only): 
• 
Work remuneration 
(including year-end 
bonus reserve) 
• 
Employer contribution to 
labor and health 
insurance 
• 
Employer contribution to 
labor pension (6% of 
insured salary) 
 
 
 
 
(2) Part-time Personnel (must 
be enrolled students): 
• 
Work remuneration 
□ Undergraduate student 
□ Master's student 
□ Other: 
___________________ 
• 
Employer contribution to 
labor and health 
insurance 
• 
Employer contribution to 
labor pension (6% of 
insured salary) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(3) Temporary Workers: 
• 
Work remuneration 
• 
Employer contribution to 
labor and health 
insurance 
• 
Employer contribution to 
labor pension (6% of 
insured salary) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(4) Professional Assistance 
Fees 
12,000 
40 
480,000  
 
 
Subtotal: 480,000 
 
2.Animal 
Experimentation 
Fees 
 
 
 
 
 
 
 
Subtotal:  
 
3.Consumables, 
Equipment, 
Books, and 
Miscellaneous 
Expenses 
Participant Stipends 
Miscellaneous: Postage and 
Telecommunications, Printing 
Costs, Copy Paper, Copying 
500 
1,000 
 
15,000 
 
210 
40 
 
1 
 
105,000 
40,000 
 
15,000 
 
 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               16 
Fees, Binding Fees, Stationery 
Costs, Poster Production Fees, 
Computer Data Statistics Fees, 
Computer Data Analysis Fees, 
Paper Submission Fees, Paper 
Publication Fees, Sectioning, 
Embedding, and Staining 
Immunology Costs. 
 
 
 
 
 
 
 
 
Subtotal: 160,000 
 
2. Research 
Equipment Costs 
(According to 
regulations, books, 
computers, and 
peripheral equipment 
are not included in the 
subsidy. Medium and 
large instruments will 
be applied for 
collectively by the 
research department, 
based on necessity, 
for shared use.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subtotal: 0 
 
Total 
640,000 
 
 
  

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               17 
6. Project Abstract 
（Please provide a summary of the key points of this project within 500 words, and create customized keywords based 
on the nature of the project.） 
 
Gastroesophageal reflux disease (GERD) poses a challenging medical condition to manage, with 
up to 40% of patients showing refractory to standard medical intervention, which usually begins with 
a proton pump inhibitor (PPI). Among these cases, esophageal disorders of gut-brain interaction 
(DGBI), such as reflux hypersensitivity and functional heartburn, or GERD patients with concurrent 
occurrences of these conditions, constitute more than 90% of the patients who did not respond to 
twice-daily PPI treatment. Esophageal visceral hypersensitivity and hypervigilance are the two 
pathways that drive esophageal DGBI and symptoms. The Rome IV esophageal disorders, 
encompassing functional chest pain, functional heartburn, globus, functional dysphagia, and reflux 
hypersensitivity, are defined by present with symptoms originating from the esophagus without 
detectable evidence of structural, inflammatory, or motor disorders. Diagnosing esophageal DGBI 
necessitates testing involving endoscopy, pH-impedance monitoring, and high-resolution manometry. 
Neuromodulators form the basis of the pharmacological strategy for managing various esophageal 
DGBI and symptoms, modulating both peripheral and central hyperalgesia. Increasing evidence 
supports the use of brain-gut behavioral therapies, such as gut-directed hypnotherapy and cognitive 
behavior therapy, as effective treatments for a variety of DGBIs. However, the efficacy of 
neuromodulators or cognitive behavior therapy in treating esophageal DGBI and related symptoms 
remains largely unexplored. The primary objective of this study is to examine the efficacy of cognitive 
behavior therapy in managing esophageal DGBI. Additionally. The findings from this study will 
contribute to a better understanding of the pathophysiology of esophageal DGBI and GERD with 
refractory symptoms. These clinical insights may then offer valuable guidance for future therapeutic 
approaches in DGBI patients who experience esophageal symptoms and do not respond to PPI 
treatment. 
 
Key words: gastroesophageal reflux disease, disorders of gut-brain interaction, neuromodulators, 
cognitive behavior therapy 
 
 
 
 
 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               18 
7. Background and Objectives of the Research Project 
（Please provide a detailed description of the background, objectives, significance of this research project, as well as the 
research status both domestically and internationally related to this project. Also, include a review of important references 
and literature.） 
 
Research Background 
◆Pathophysiological Mechanisms and Importance of Gastroesophageal Reflux Disease (GERD) 
Gastroesophageal reflux disease (GERD) is defined as a condition where stomach contents 
flow back into the esophagus, resulting in symptoms or mucosal injury. Common typical symptoms 
include heartburn or acid reflux, while atypical symptoms may include chest tightness, a sensation 
of a foreign body in the throat, hoarseness, or chronic cough. Clinically, GERD is a common 
chronic disease. In the United States, where symptoms occur at least once a week, up to 30% of 
adults are affected by GERD; in East Asia, the prevalence is 5-10%, but there is a growing trend in 
its incidence. 
There are many possible pathogenic mechanisms for GERD, including lower esophageal 
sphincter (LES) dysfunction or structural abnormalities, ineffective esophageal motility, esophageal 
mucosal integrity defects, esophageal hypersensitivity, the formation of acid pockets after meals, 
the composition of gastric refluxate, and delayed gastric emptying. Currently, the most common 
diagnostic method involves observing damage to the distal esophageal mucosa through endoscopy 
or confirming abnormal gastric acid exposure via a 24-hour pH monitoring test. Based on the results 
of endoscopy and esophageal pH monitoring, GERD patients can be classified into two categories: 
erosive esophagitis (EE) and non-erosive reflux disease (NERD). 
Repeated gastric acid exposure to the distal esophagus not only causes mucosal damage but 
may also lead to severe complications such as esophageal stricture, Barrett’s esophagus, and 
esophageal adenocarcinoma. Statistics show that in the United States, medical and non-medical 
losses due to GERD exceed $930 million annually. Therefore, GERD has become an important 
issue both clinically and in national public health policies in recent years. 
 
◆ Disorders of gut-brain axis interaction in esophagus 
Disorders of gut-brain axis interaction (DGBI) refer to gastrointestinal diseases that present 
with symptoms but no organic abnormalities, which were previously referred to as functional 
gastrointestinal disorders. In the recent Rome IV criteria，11 In the esophageal context, the Rome 
IV criteria define five conditions: functional chest pain, reflux hypersensitivity (RH), functional 
heartburn (FH), globus, and functional dysphagia. Epidemiologically, the prevalence of esophageal 
disorders related to gut-brain axis interaction is still not well understood. Past population-based 

Version Date：(Version 8, 11/19/2024) 
E6A0021096-10                                                                               19 
studies have shown that the prevalence of non-cardiac chest pain is approximately 19-33%，12,13 
Further generation-based analysis of the population with psychogenic chest pain revealed that 
approximately 32-35% of them were diagnosed with functional chest pain.14 In terms of reflux 
hypersensitivity, among patients with non-erosive mucosal damage in the esophagus, approximately 
10-36% are diagnosed with esophageal hypersensitivity.15,16 Functional heartburn has an unknown 
prevalence due to the limitations of current diagnostic tools and receiver operating characteristic 
(ROC) curves. Globus, on the other hand, is a commonly encountered disorder of gut-brain axis 
interaction in clinical practice. Research reports indicate that 46% of healthy adults have 
experienced globus at some point.17 Functional dysphagia is the least common, and its prevalence 
remains unclear to this day. 
In terms of definition, patients must have chronic esophageal symptoms lasting at least three 
months, with the first occurrence of symptoms being more than six months before the diagnosis of 
the disease. Additionally, structural, inflammatory, motility, and metabolic abnormalities in the 
esophagus must be excluded.1 Therefore, to diagnose esophageal disorders related to gut-brain axis 
interaction, upper gastrointestinal endoscopy, esophageal pH-impedance testing, and high-resolution 
esophageal manometry are required to exclude other esophageal diseases that may cause similar 
symptoms. Regarding the pathophysiological mechanisms, it is currently believed that they may be 
related to esophageal visceral hypersensitivity and hypervigilance, but the exact mechanisms still 
require further research for confirmation. In terms of diagnostic criteria, according to the Rome IV 
criteria, the definition is as follows:11 
 Functional Chest Pain: 
(1) Occurs ≥1 time per week with non-cardiac chest pain or chest tightness; 
(2) No associated heartburn or dysphagia; 
(3) Symptoms are not related to gastroesophageal reflux disease (GERD) or eosinophilic 
esophagitis; 
(4) No significant esophageal motility disorders. 
 Functional Heartburn: 
(1) Occurs ≥2 times per week with substernal symptoms such as heartburn or chest pain; 
(2) Symptoms do not improve with antisecretory therapy; 
(3) Symptoms are not related to gastroesophageal reflux disease (GERD) or eosinophilic 
esophagitis; 
(4) No significant esophageal motility disorders. 
 Reflux Hypersensitivity (Esophageal Hypersensitivity): 
(1) Occurs ≥2 times per week with substernal symptoms such as heartburn or chest pain; 
(2) Endoscopy is normal, and eosinophilic esophagitis must be excluded; 
(3) No significant esophageal motility disorders; 

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(4) Esophageal pH or pH-impedance testing shows normal acid exposure levels, but reflux 
is associated with symptoms. 
 Globus: 
(1) Occurs ≥1 time per week with persistent or intermittent, non-painful sensation of a lump 
in the throat, with no organic lesions confirmed through clinical examination, laryngoscopy, 
or endoscopy; 
(2) Symptoms occur between meals, with no dysphagia or odynophagia, and no gastric 
metaplasia in the proximal esophagus (gastric inlet patch); 
(3) Symptoms are not related to gastroesophageal reflux disease (GERD) or eosinophilic 
esophagitis; 
(4) No significant esophageal motility disorders. 
 Functional Dysphagia:  
(1) Occurs ≥1 time per week with a sensation of obstruction or abnormal feeling when 
solids or liquids pass through the esophagus; 
(2) Symptoms are not related to esophageal mucosal or structural abnormalities; 
(3) Symptoms are not related to gastroesophageal reflux disease (GERD) or eosinophilic 
esophagitis; 
(4) No significant esophageal motility disorders.     
 
Figure 1: Diagnostic Spectrum Classification of Gastroesophageal Reflux Disease (GERD) and 
Disorders of Gut-Brain Axis Interaction (DGBI). 
 
 
◆ Physiological Tests for Diagnosing Gastroesophageal Reflux Disease (GERD) and Disorders 
of Gut-Brain Axis Interaction (DGBI) 
The current diagnosis of gastroesophageal reflux disease (GERD) spectrum disorders is based 
on endoscopic examination, esophageal pH (or pH-impedance) testing results, and the association 
between reflux and symptoms. Among these, esophageal pH testing, specifically the acid exposure 
time (AET), is the most important pathophysiological parameter used to differentiate GERD from 
disorders of gut-brain axis interaction (DGBI).18 The measurement method involves calculating the 
percentage of time during a 24-hour monitoring period in which the distal esophageal pH value is less 

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than 4. The Lyon Consensus on the diagnosis of gastroesophageal reflux disease (GERD) states that 
an acid exposure time (AET) of less than 4% is considered physiological reflux, while an AET greater 
than 6% is considered pathological reflux. Additionally, if the total number of reflux episodes in 24 
hours is less than 40, it is considered normal, while more than 80 episodes is considered abnormal.8 
The combination of parameters such as acid exposure time (AET), number of acid reflux episodes, 
number of acid reflux episodes lasting more than five minutes, and the longest reflux episode duration 
can be used to assess the severity of reflux.19 By combining esophageal pH testing with impedance 
values, it is possible to detect the direction of reflux, as well as the reflux of weakly acidic, alkaline 
fluids, or gases.20 During the detection period, patients are required to record all esophageal symptoms 
occurring during the esophageal pH-impedance testing. The physician will then compare these 
recorded symptoms with the reflux events documented by the pH-impedance monitor to calculate the 
association between reflux and symptoms (Symptom Association Probability, SAP, and Symptom 
Index, SI).21 
Based on the above criteria for esophageal pH testing and endoscopic examination results, 
patients with esophageal reflux symptoms can be classified into erosive esophagitis, non-erosive 
reflux disease, esophageal hypersensitivity, and functional heartburn. Erosive esophagitis is 
characterized by visible mucosal damage at the distal esophagus during endoscopy; non-erosive 
reflux disease is identified by normal mucosa on endoscopy and pathological prolongation of the acid 
exposure time (AET) at the distal esophagus on esophageal pH testing; esophageal hypersensitivity 
presents with a normal AET, but the symptoms are associated with reflux events (refluxate may be 
acidic, weakly acidic, or weakly alkaline) as seen on pH-impedance testing; functional heartburn 
occurs when there are symptoms of gastroesophageal reflux disease, but both endoscopic examination 
and AET are normal. For disorders of gut-brain axis interaction, including functional chest pain, 
globus, and functional dysphagia, in addition to normal endoscopic and AET results, patients must 
not have significant esophageal motility disorders and must meet the diagnostic criteria related to 
esophageal symptoms, as well as the onset and duration of symptoms.  
Current diagnostic tools, such as questionnaires, proton-pump inhibitor trials, and endoscopic 
examination, have low sensitivity and specificity for diagnosing gastroesophageal reflux disease 
(GERD). While esophageal pH (or pH-impedance) testing is considered the gold standard for 
diagnosing GERD, it can only detect and diagnose reflux events that occur during the test period. 
Among these, catheter-based esophageal pH testing is limited because it can only detect reflux 
activity during the 24-hour test period. Additionally, patients may experience discomfort from the 
catheter, which could lead to changes in their daily activities, thereby potentially affecting the 
diagnostic results to varying degrees.。22-23 The 96-hour wireless capsule-based esophageal pH 
monitoring, compared to the 24-hour esophageal pH-impedance testing, not only avoids the 
discomfort caused by the catheter but also extends the monitoring period to 96 hours. Previous studies 

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have indicated that up to one-third of patients diagnosed with functional heartburn based on 24-hour 
esophageal pH-impedance testing had their diagnosis corrected to non-erosive reflux disease after 
undergoing 96-hour wireless capsule-based esophageal pH monitoring.24 However, the 24-hour 
esophageal pH-impedance testing can improve the probability of diagnosing or excluding 
gastroesophageal reflux disease (GERD) by calculating the mean nocturnal baseline impedance 
(MNBI). The mean nocturnal baseline impedance is derived by recording the 10-minute average 
impedance values during the patient's sleep at three one-hour intervals (1:00, 2:00, 3:00). Recent 
studies have indicated that the mean nocturnal baseline impedance is associated with mucosal 
integrity, acid exposure time, and reflux symptoms.25, 26 
◆The Treatment Dilemma of Refractory Gastroesophageal Reflux Disease and Esophageal 
Brain-Gut Axis Communication Disorders 
  Proton pump inhibitors (PPIs) are the primary medications used to treat gastroesophageal reflux 
disease. Although they are highly effective in improving typical heartburn symptoms in patients with 
erosive esophagitis，27-29 However, their effectiveness in treating non-erosive gastroesophageal reflux 
disease (NERD) is less than ideal. According to statistics, up to 50% of patients treated with proton 
pump inhibitors (PPIs) for suspected reflux symptoms still experience persistent symptoms.1,30 
Studies have indicated that most gastroesophageal reflux disease (GERD) patients who are 
unresponsive to proton pump inhibitor (PPI) treatment have a normal acid exposure time (AET).32 In 
patients with heartburn who remain unresponsive to high-dose proton pump inhibitor (PPI) treatment, 
more than 90% are diagnosed with esophageal hypersensitivity or functional heartburn.31,32 In 
addition, patients with pathological reflux may also have concurrent esophageal brain-gut axis 
communication disorders. The complex pathophysiological mechanisms of gastroesophageal reflux 
disease (GERD) and the limited understanding of brain-gut interaction contribute to the poor 
treatment outcomes in such patients. Recent consensus suggests that non-reflux factors, such as 
altered perception or visceral hypersensitivity, may be associated with the refractory symptoms of the 
esophagus.33 
◆Treatment Strategies for Refractory Gastroesophageal Reflux Disease and Esophageal 
 Brain-Gut Axis Communication Disorders 
  The treatment strategies for refractory gastroesophageal reflux disease (GERD) and esophageal 
brain-gut axis communication disorders remain unclear. Currently, it is believed that esophageal 
hypervigilance, anxiety, and autonomic arousal are the primary factors influencing the severity of 
symptoms and the response to reflux burden. The Esophageal Hypervigilance and Anxiety Scale 
(EHAS) has been recently validated in studies as an effective tool for assessing esophageal 
hypersensitivity.34 Therefore, it is considered a helpful tool in diagnosing esophageal brain-gut axis 
communication disorders. Neuromodulators are medications used clinically to treat these disorders. 

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Previous research has shown that neuromodulators can effectively reduce symptoms in patients with 
irritable bowel syndrome (IBS) or functional dyspepsia by modulating visceral hypersensitivity 
through central and peripheral mechanisms.35,36 Therefore, using neuromodulators to regulate visceral 
hypersensitivity and esophageal hypervigilance in esophageal brain-gut axis communication 
disorders is considered a feasible strategy. However, a systematic review of the literature shows that 
among the few available randomized controlled trials, the efficacy of neuromodulators in the various 
subtypes of esophageal brain-gut axis communication disorders is inconsistent.37 Therefore, whether 
neuromodulators can be widely used in the treatment of these disorders still requires more supporting 
evidence. 
Cognitive Behavioral Therapy (CBT) is a form of psychological treatment that functions as a 
brain-gut axis intervention. It can modify the pain perception pathways of the brain-gut axis, reduce 
hypervigilance and symptom-specific anxiety, and is considered effective in improving chronic 
esophageal symptoms associated with disorders of brain-gut axis communication. 
This approach includes the measurement of Heart Rate Variability (HRV), which involves collecting 
raw electrocardiogram signals through a biofeedback system or using photoplethysmography (PPG) 
sensors to detect pulse wave signals. These signals are then converted into HRV indicators, which 
serve as markers of autonomic nervous system activity. 
Heart Rate Variability Biofeedback (HRVB) can enhance HRV indices and has been shown to be 
effective in individuals with physical illnesses, psychological disorders, and even in healthy 
populations. 38, 39 
 Recent studies have shown that Cognitive Behavioral Therapy (CBT) can improve esophageal 
symptoms and quality of life in individuals with supragastric belching and non-erosive reflux disease 
(NERD). 40-42 Currently, Cognitive Behavioral Therapy (CBT) for gastrointestinal disorders typically 
involves 6 to 8 therapy sessions. In this study, participants will undergo either six weeks of CBT or 
lifestyle management, administered by psychologists trained in CBT and conducted in accordance 
with the clinical guidelines of the American Gastroenterological Association (AGA). 43 
Figure 2. The primary goal of Cognitive Behavioral Therapy (CBT) is to modify maladaptive thoughts and 
behaviors in order to reduce esophageal hypervigilance. 

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Research Objectives 
The objectives of this study： 
Exploring the Effects of Cognitive Behavioral Therapy on Disorders of Esophageal Brain-Gut 
Axis Dysregulation.  
Hypothesis: 
(1) Patients with disorders of esophageal brain-gut axis dysregulation often experience esophageal 
symptoms due to visceral hypersensitivity and esophageal hypervigilance, which can negatively 
affect their physical and mental health, sleep, and quality of life. Cognitive Behavioral Therapy (CBT) 
can help alleviate these symptoms and reduce their impact. 
(2) CBT has been shown to improve symptoms across different subtypes of disorders involving 
esophageal brain-gut axis dysregulation. 
 
8. Research Methods, Procedures, and Execution Progress 
1. Please describe in detail the research methods adopted in this project and the reasons for 
choosing them. 
2. Potential challenges and solutions expected during the project. 
3. If this is a continuous project, please also attach the progress report from the previous year or 
primary data. 
 
Research Method 
Participant 
This project is a multi -center study. we will recruit cases from three medical centers in 
Taiwan, We plan to enroll a total of 120 participants, including 40 from our hospital, 40 from 
Kaohsiung Medical University Hospital, and 40 from E-Da Hospital. 
   This study is expected to last for 2 years, with the study period ending on December 31, 2025. 
We intend to recruit participants with esophageal symptoms related to disorders of the gut-brain axis 
communication from the Gastroenterology outpatient clinics. 
 
Inclusion criteria for participants： 
1. Age between 18 and 75 years, with clear consciousness and willingness to sign the informed 
consent form. 

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2. Participants with chronic esophageal symptoms related to esophageal-brain-gut axis 
communication disorders (such as heartburn, acid reflux, sensation of a foreign body in the 
throat, difficulty swallowing, chest pain, and chest tightness). 
Exclusion criteria for participants： 
1. Esophageal stricture, or a history of esophageal, gastrointestinal, or throat surgery. 
2. Structural esophageal diseases (e.g., diverticula, esophageal rings), infectious esophagitis, 
erosive esophagitis, eosinophilic esophagitis. 
3. Non-erosive gastroesophageal reflux disease or significant esophageal motility disorders. 
4. A history or current diagnosis of esophageal, gastrointestinal, or other organ malignancies. 
5. Significant endocrine or rheumatic autoimmune diseases that may affect gastrointestinal 
motility. 
6. Continuous use of medications that may affect esophageal motility (e.g., anticholinergics, 
morphine-like drugs, nitrates, calcium channel blockers) within the past month. 
7. Use of antidepressants, selective serotonin reuptake inhibitors, or other psychiatric medications 
within the past three months. 
8. Pregnant or breastfeeding women. 
9. Individuals with mental disorders or those 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. 
 

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Research Design Flowchart 
 
 
 
Steps to Follow 
In this study, All participants will undergo questionnaire assessments and heart rate variability 
measurements before treatment. The questionnaires include the Gastroesophageal Reflux Disease 
Questionnaire (GERDQ), PROMIS GERD, DSI & GSS, RSI, Brief Esophageal Dysphagia 
Questionnaire (BEDQ), Esophageal Hypervigilance and Anxiety Scale (EHAS), Visceral Sensitivity 
Index (VSI), Sleep and Mental Health Questionnaires (Sleep Habits Questionnaire PSQI, Taiwanese 
Depression Questionnaire TDQ, State-Trait Anxiety Inventory STAI, Functional Dyspepsia (FD) 
Questionnaire, Irritable Bowel Syndrome (IBS) Questionnaire, Quality of Life Questionnaire SF-12, 
and Northwest Esophageal Quality of Life Scale (NEQOL). Heart rate variability will be measured 
using the non-invasive "Mind Technology" biofeedback system (Taiwan FDA Medical Device 
Certification No. 011374). 
Following this, a single-blind trial will be conducted with computer-generated random allocation. 
Participants will receive either 6 weeks of Cognitive Behavioral Therapy (CBT) or 6 weeks of 
lifestyle management (sham control), with one 1-hour session per week. After 6 weeks of counseling, 
participants will undergo a final questionnaire assessment and heart rate variability measurement after 
the 12th week of enrollment. The questionnaires and measurements will take approximately 20 to 30 
minutes to complete, marking the end of the trial. 
Cognitive Behavioral Therapy (CBT) will be carried out according to the following steps： 
(1) Education and Initial Follow-up 

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(2) Heart Rate Variability and Breathing Introduction 
(3) Cognitive Restructuring and Breathing Application 
(4) Cognitive Diffusion and Behavioral Experiments 
(5) Problem-Solving and Emotion-Focused Coping Strategies 
(6) End of Treatment and Relapse Prevention 
Lifestyle Management (Sham Control) will be carried out according to the following steps： 
(1) Education and Initial Follow-up 
(2) Dietary Habits: What, When, Where, Why 
(3) Changing My Diet: Strategies and Barriers 
(4) Lifestyle Factors: Alcohol, Smoking, and Sugar 
(5) Lifestyle Factors: Sleep and Exercise 
(6) End of Treatment and Relapse Prevention 
In this study, we will use non-invasive physiological signal sensors connected to a biofeedback 
system to measure the participants' physiological signals, including electrocardiogram (ECG) and 
breathing. Before measurement, participants will first apply ECG electrodes for a two-lead ECG 
measurement, which will then be converted into heart rate variability (HRV) indicators. 
Simultaneously, a non-invasive breathing sensor will be used to measure the respiratory rate per 
minute. Except for a very small number of participants who may experience allergic reactions to the 
ECG electrodes, the likelihood of side effects is less than 1%. 
 
Multicenter Communication and Coordination Method 
The hospital directors of the participating institutions and the principal investigator, Dr. Lei Wei-
Yi, will communicate and coordinate via email and a Line group established for the project. The 
research data collected by each center will be managed and stored by the respective center's director. 
The hospital directors will assist in consolidating the research data from their institution, and the 
electronic data will be coded for identification. After the data is compiled, it will be sent back to the 
principal investigator. Additionally, the research physicians and staff at each participating center will 
have regular video conferences (every 2 months) to discuss and report on the progress of the study. 
 
Statistical Analysis 
All data will undergo normality testing using the Kolmogorov-Smirnov test. If continuous 
variables follow a normal distribution, they will be expressed as means and standard deviations; if 
not, they will be presented as medians and interquartile ranges. 

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For categorical variables, the Chi-square test or Fisher's exact test will be used for analysis. 
Continuous variables that are normally distributed will be analyzed using the unpaired t-test, while 
non-normally distributed continuous variables will be analyzed using the Mann-Whitney U test. 
For comparisons involving more than three groups, if the data are normally distributed, an 
ANOVA with post hoc tests will be conducted. If the data are non-normally distributed, the 
Kruskal-Wallis test will be applied. A p-value of less than 0.05 will be considered statistically 
significant. 
Statistical analyses will be performed using SPSS 19 for Windows (SPSS, Inc., Chicago, IL, 
USA). 
 
Clinical Significance and Originality of This Study 
1. The originality of this study lies in its use of visceral sensitivity, mind-body connection, 
esophageal 
hypersensitivity, 
anxiety 
questionnaires, 
and 
functional 
gastrointestinal 
questionnaires to explore the effects of neuromodulators on diseases related to esophageal-brain-
gut axis communication abnormalities. Patients with such conditions often experience more 
severe esophageal symptoms due to excessive visceral sensitivity and esophageal hypersensitivity.  
2. This study aims to establish a model for Cognitive Behavioral Therapy (CBT) in disorders of 
esophageal brain-gut axis dysregulation. Our research examines the role of CBT in esophageal 
brain-gut axis dysregulation and refractory gastroesophageal reflux disease (GERD). The results 
obtained from this study will deepen our understanding of the pathophysiological mechanisms of 
esophageal brain-gut axis dysregulation and refractory GERD. The findings will help elucidate 
the etiology of refractory GERD, particularly when patients with GERD also present with 
esophageal brain-gut axis dysregulation, which leads to a lowered threshold for esophageal 
symptom perception. This condition can be reversed and improved through the aforementioned 
treatments. Furthermore, it will assist in early clinical intervention for patients with brain-gut axis 
communication disorders, enabling the establishment of personalized treatment strategies and the 
achievement of precision medicine for such patients. 
 
 
 
 
 

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9.Expected Work Items and Specific Outcomes 
(1) Please list the expected tasks to be completed within the execution period. 
(2) Expected contributions to academic research and other applied areas. 
(3) Expected training that participants will receive. 
(1)  Work items expected to be completed. 
In this study, we will also explore the effects of Cognitive Behavioral Therapy (CBT) on 
disorders of esophageal brain-gut axis dysregulation, as well as its impact on physical and mental 
health and quality of life. 
(2)  The anticipated contributions to academic research, national development, and other 
applications. 
1. The data obtained from this study will allow us to understand the role of visceral sensitivity and 
esophageal awareness in esophageal-brain-gut axis communication abnormalities and refractory 
gastroesophageal reflux disease. It will also help us establish the role of Cognitive Behavioral 
Therapy (CBT) in esophageal-brain-gut axis communication abnormalities and their impact on the 
regulation of brain-gut axis communication. 
2. Clinically, patients with esophageal-brain-gut axis communication abnormalities often experience 
delayed diagnoses and poor treatment outcomes. The results of this study will enable us to 
intervene early and accurately in such brain-gut axis communication abnormality cases, helping 
clinical healthcare providers develop precise and effective treatment strategies. 
(3)  The expected training for the participating staff. 
In addition to receiving general research training (such as experimental design and execution, 
questionnaire creation and completion, result analysis and statistics, chart creation, oral presentations, 
writing papers, and the submission process), participants will also have the opportunity to learn more 
specialized research design and numerical analysis techniques. 

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