Randomized Controlled Study of Optical 3D Navigated Repetitive Transcranial Magnetic Stimulation for Achalasia.

Study Overview
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Brief Summary
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The goal of this clinical trial is to investigate the clinical efficacy of repetitive transcranial magnetic stimulation in the treatment of achalasia in patients diagnosed with achalasia by comprehensive evaluation of clinical symptoms, HREM, and barium meal examination, optimize rTMS treatment parameters, and provide an effective and noninvasive new treatment strategy for achalasia. The main questions it aims to answer are: To investigate the clinical efficacy of individualized treatment of achalasia with optical 3D navigation repetitive transcranial magnetic stimulation. Optimize rTMS parameters to achieve the best clinical treatment. Participants will need to fill out the Eckardt score scale and SF-36 quality of life scale, undergo cranial T1 structural magnetic resonance for functional connectivity analysis, and select the brain region with the strongest positive functional connectivity to the DMV as the rTMS target. All patients were randomly divided into four groups: sham-rTMS group, 5Hz-rTMS group, 10Hz-rTMS group, and 30Hz-rTMS group, and each group received acute and chronic stimulation, respectively. In the acute stimulation stage, patients only need to do rTMS once, and HREM and HRV detection are given before and after rTMS (stimulation for 1s, interval for 4s, 10 pulses per second, receiving a total of 3000 pulses); in the chronic stimulation stage, patients receive 25 minutes of rTMS actual stimulation or sham stimulation each time, lasting for 20 times, which is completed within 30 days, and the actual stimulation parameters are the same as those of acute stimulation, and the sham stimulation coil is consistent with the appearance and sound of proper stimulation, but there is no substantial stimulation. High-definition esophageal manometry, timed barium meal, heart rate coefficient of variation, and serum neurotransmitters were performed before and after chronic stimulation. Finally, a weekly telephone follow-up was performed for 12 weeks, including Eckardt score and SF-36 quality of life scale.

Detailed Description
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Study hypothesis: By analyzing the strongest resting-state functional connectivity between DMV and right precentral gyrus, left postcentral gyrus, and left brain leads in achalasia patients, individualized rTMS treatment with optical 3D navigation was applied to relax LES and relieve the clinical symptoms of dysphagia. Statistical methods: SPSS 25.0 software was used to process the data, symptom score, manometry parameters, serum transmitters and other quantitative indicators. If they met the normal distribution, they were expressed as Mean ± SD. The t-test was performed for the comparison between the two groups; if they did not obey the normal distribution, the median (quartile) was used for statistical description. The rank sum test was used for the comparison between the two groups. Enumeration data were described using number of cases (percentage), and X2 test, corrected X2 test, or Fisher exact test were performed for comparison between the 2 groups.

Official Title
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To Investigate the Clinical Efficacy of Optical 3D Navigation Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Achalasia, Optimize the Treatment Parameters, and Provide a Noninvasive Treatment Strategy for Achalasia

Conditions
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Transcranial Magnetic Stimulation, Repetitive, Vagus Nerve Motor Disorder, Functional Magnetic Resonance Imaging, Esophageal Achalasia

Intervention / Treatment
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* Device: Repetitive transcranial magnetic stimulation
* Device: Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged more than 18 years old, less than 75 years old; Clinical symptoms evaluation, HREM, esophageal barium meal examination confirmed the diagnosis of achalasia; Willing to sign informed consent. Exclusion Criteria: Presence of metal hardware in close contact with the discharge coil (e.g., cochlear implant, internal pulse generator, or drug pump). Note: Cochlear implants include electrodes, magnets, loop antennas, and electronic chips under the scalp implanted in the cochlea; Intracranial metal implants; Patients with cardiac pacemakers, vagal nerve stimulation (VNS) systems, spinal cord stimulators, and deep brain stimulation implanted with pulse generators should be used with caution; People at higher risk of noisy hearing loss and patients with hypoacusis symptoms should be used with caution; Pregnancy; Severe or recent heart disease; Personal history of epilepsy, use of known drugs that lower the seizure threshold, and other factors that may lower the seizure threshold (e.g., lack of sleep, infection, and alcohol abuse); Increased intracranial pressure; Acute phase of intracranial infection and hemorrhagic disease; Contraindications to MRI examination or claustrophobia; Refusal to sign informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In patients with achalasia diagnosed by clinical symptoms, HREM and barium meal examination, functional connectivity analysis of DMV with three brain regions (precentral gyrus, postcentral gyrus and insula) was performed by scanning T1 structural magnetic resonance imaging, and brain regions with the strongest positive functional connectivity with DMV were selected as individualized rTMS targets by optical 3D navigation. All patients were randomly divided into four groups: sham-rTMS group, 5Hz-rTMS group, 10Hz-rTMS group, and 30Hz-rTMS group, and each group received acute and chronic stimulation, respectively.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham group<br>Intervention Name and Specification: Placebo coil (Magstim Company, Whitland, UK): looks and sounds consistent with true coil but does not produce current stimulation. | Device: Sham<br>* Placebo coil (Magstim Company, Whitland, UK):<br>|
| Experimental: rTMS group<br>5Hz-rTMS group 10Hz-rTMS group 30Hz-rTMS group Intervention Name and Specification: Transcranial magnetic stimulator (M-100 Ultimate, Yingzhi Technology Co., Ltd., China) 70 mm diameter figure-of-eight coil (BY90A, Yingzhi Technology Co., Ltd., China). Each group received acute and chronic stimulation, respectively. In the acute stimulation stage, patients only needed to do rTMS once, and HREM and HRV were administered before and after rTMS; in the chronic stimulation stage, patients received 25 minutes of rTMS true stimulation each time a day for 20 times, which was completed within 30 days, and the true stimulation parameters were the same as those of acute stimulation. | Device: Repetitive transcranial magnetic stimulation<br>* Intervention Name and Specification Transcranial magnetic stimulator (M-100 Ultimate, Yingzhi Technology Co., Ltd., China) . 70-mm-diameter figure-of-eight coil (BY90A, Yingzhi Technology Co., Ltd., China). 3) Placebo coil (Magstim Company, Whitland, UK): the appearance and sound were consistent with the true coil, but no current stimulation was produced.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Eckardt score | The Eckardt scoring system is used to assess the severity of symptoms, with 0 to 1 in grade 0, 2 to 3 in grade I., 4 to 6 in grade II., and > 6 in grade III. The more severe the symptoms, the higher the score, and can also be used for efficacy assessment. | Measured immediately after intervention. | 
| Real-time esophageal barium meal examination | The severity of the patient 's condition and the therapeutic effect were evaluated by defining the height and maximum width of the residual barium area. | Measured immediately after intervention. | 
| High-resolution esophageal manometry（HREM） | HREM is the gold standard for the diagnosis of achalasia of cardia (AC), which can assess the relaxation ability of the lower esophageal sphincter (LES) and the contraction ability of the esophageal body. HREM dynamically collects the mean pressure data of multiple parts of the whole esophagus in real time, and converts the linear manometry pattern into color pressure topography. The basic manometry parameters include integrated relaxation pressure (IRP) and lower esophageal sphincter pressure (LESP), which can more truly reflect the relaxation function of the gastroesophageal junction (EGJ) and are the key indicators for the diagnosis of AC. | Measured immediately after intervention. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart rate variability assessment | Dynamic electrocardiogram recording analysis of sympathetic vagal activity. | Measured immediately after intervention. | 
| Neurotransmitter detection analysis | Serum ACh, NO and VIP | Measured immediately after intervention. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Achalasia, rTMS, fMRI, Non-invasive