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The goal of this clinical trial is to learn if repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive brain stimulation technique, works to treat Metabolic dysfunction-associated and alcohol-associated liver disease (MetALD). The main questions it aims to answer are:
Researchers will compare three different types of stimulation:
Participants will:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Conventional rTMS | Active Comparator |
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| Sham rTMS | Sham Comparator |
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| Active rTMS | Experimental |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Individually Targeted rTMS | Device | Participants will receive individualized transcranial magnetic stimulation (TMS) based on neuroimaging-guided localization of the nucleus accumbens (NAc). After the first MRI scan, participants will be randomized by an independent researcher responsible for data analysis. The individualized stimulation coordinates will be provided to the TMS operator before treatment. Intervention will be delivered using intermittent theta-burst stimulation (iTBS): the coil will be placed tangentially to the scalp over the individualized target. Stimulation parameters: 90% resting motor threshold (RMT); bursts of 3 pulses at 50 Hz; bursts repeated at 5 Hz; a total of 1800 pulses per session; stimulation duration 570 seconds. Each participant will receive 20 sessions in total, with at least 2 treatment days per week (2 sessions/day, 4 sessions/week). MRI and clinical assessments will be repeated at mid-treatment and after treatment completion, with follow-up clinical evaluations at 1, 3, and 6 months. |
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Liver Fat Content (LFC) From Baseline to End of Treatment as Measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) | From baseline to the end of treatment (Week 4) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Controlled Attenuation Parameter (CAP, dB/m) From Baseline as Assessed by Vibration-Controlled Transient Elastography (FibroScan® VCTE) | From baseline to mid-treatment (Week 2), end of treatment (Week 4), and at 1-, 3-, and 6-month follow-up | |
| Change in Liver Stiffness Measurement (LSM, kPa) From Baseline as Assessed by FibroScan® VCTE |
| Measure | Description | Time Frame |
|---|---|---|
| Resting-State Functional Connectivity (rs-FC) Measured by fMRI | Resting-state functional connectivity (rs-FC) will be assessed using functional magnetic resonance imaging (fMRI). This measures the temporal correlation of spontaneous brain activity between different neural regions, forming functional networks (e.g., Default Mode Network, Executive Control Network). The strength of connectivity is represented by correlation coefficients (z-values). A higher absolute value indicates stronger functional connectivity. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Junping Shi | Contact | +86 13957121199 | 20131004@hznu.edu.cn |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Affiliated Hospital of Hangzhou Normal University | Hangzhou | Zhejiang | 310015 | China |
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| Conventional rTMS | Device | Conventional rTMS is applied to the left dorsolateral prefrontal cortex (DLPFC) using the standard 5 cm rule for scalp-based localization. Stimulation is delivered with intermittent theta-burst stimulation (iTBS) at 90% resting motor threshold (RMT), 3 pulses at 50 Hz per burst, repeated at 5 Hz, for a total of 1800 pulses per session. Each session lasts about 570 seconds. Participants complete 20 sessions over 4 weeks, with 2 sessions per day on 2 days per week. |
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| Transcranial Magnetic Stimulation Sham | Device | Sham rTMS is delivered using a sham coil or low-intensity stimulation (10% RMT) to mimic the clicking sounds and scalp sensations of active rTMS without producing cortical activation. The sham sessions are matched to the active treatment in frequency, duration, and total number: 20 sessions in 4 weeks (2 sessions/day, 2 days/week, 570 seconds per session). |
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| From baseline to mid-treatment (Week 2), end of treatment (Week 4), and at 1-, 3-, and 6-month follow-up |
| LFC From Baseline as Measured by MRI-PDFF | From baseline to the end of treatment (Week 4) |
| Proportion of Participants Achieving ≥30% or ≥50% Reduction in LFC From Baseline | From baseline to the end of treatment (Week 4) |
| Change in Serum Levels of Liver Enzymes (ALT, AST, ALP, GGT [U/L]) From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Serum Level of Albumin From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in International Normalized Ratio (INR) From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Prothrombin Time (PT) From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Serum Level of Total Bilirubin (TBIL) From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Proportion of Participants With ALT Reduction >17 U/L From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Glucose Metabolism Markers (HOMA-IR [Index]; HOMA-β [Index]) From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Glucose Metabolism Markers (HbA1c [%]) From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Fasting Plasma Glucose (FPG) From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Fasting Insulin From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Concentration of Conventional Lipid Panel (TC, TG, HDL-C, LDL-C, non-HDL-C, VLDL-C [mmol/L]) From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Concentration of Apolipoproteins (Apo A1, Apo B [g/L]) From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Serum Lipoprotein(a) (Lp(a)) Concentration From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Serum Free Fatty Acids (FFA) Concentration From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Body Weight [kg] From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in BMI [kg/m²] From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Body Circumferences (Waist, Hip) [cm] From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Waist-to-Hip Ratio From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in General Food Craving Questionnaire-Trait (G-FCQ-T) Total Score From Baseline | G-FCQ-T The General Food Craving Questionnaire-Trait (G-FCQ-T) is a self-reported instrument used to assess the general tendency to experience food cravings. It comprises 21 items. Participants rate each item on a 6-point Likert scale ranging from 1 ("Never") to 6 ("Always"). The total score is the sum of all item ratings, with a possible range from 21 to 126. A higher total score indicates a more severe trait propensity for food craving. | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in General Food Craving Questionnaire-State (G-FCQ-S) Total Score From Baseline | G-FCQ-S The General Food Craving Questionnaire-State (G-FCQ-S) is a self-reported instrument used to assess the current, momentary state of food craving. It comprises 15 items. Participants rate each item on a 6-point Likert scale ranging from 1 ("Strongly Disagree") to 6 ("Strongly Agree"). The total score is the sum of all item ratings, with a possible range from 15 to 90. A higher total score indicates a more intense current state of food craving. | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Score on Visual Analogue Scale (VAS) for Subjective Food Craving From Baseline | Subjective food craving is assessed using a Visual Analogue Scale (VAS). Participants indicate their current, momentary level of food craving by marking a point on a 100-mm horizontal line. The left endpoint (0 mm) is labeled "No food craving at all," and the right endpoint (100 mm) is labeled "The most intense food craving imaginable." The score is determined by measuring the distance from the left endpoint to the participant's mark, ranging from 0 to 100. A higher score indicates a more intense subjective feeling of food craving. | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Caloric intake recorded by the Mint Health App From Baseline | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Alcohol Use Disorders Identification Test (AUDIT) Score From Baseline | The Alcohol Use Disorders Identification Test (AUDIT) is a simple, self-reported screening tool developed by the World Health Organization (WHO) to identify hazardous and harmful patterns of alcohol consumption. The questionnaire consists of 10 items. The first 8 items are scored on a scale from 0 to 4. Items 9 and 10 are scored 0, 2, or 4. The total score is the sum of all item ratings, with a possible range from 0 to 40. A higher total score indicates a greater likelihood of hazardous and harmful alcohol use, as well as possible alcohol dependence. | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Penn Alcohol Craving Scale (PACS) Score From Baseline | The Penn Alcohol Craving Scale (PACS) is a self-reported questionnaire designed to measure the intensity of an individual's craving for alcohol over the past week. The scale consists of 5 items assessing the frequency, duration, and intensity of craving, the ability to resist drinking, and the overall rating of craving. Each item is rated on a 6-point scale from 0 to 6, with varying verbal anchors for each item (e.g., "Never" to "Nearly All the Time"). The total score is the sum of all 5 item ratings, with a possible range from 0 to 30. A higher total score indicates a more severe level of subjective alcohol craving. | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| Change in Alcohol Consumption Assessed by the Timeline Followback (TLFB) Method From Baseline | Alcohol consumption is assessed using the Timeline Followback (TLFB) method, a structured interview that provides a quantitative estimate of an individual's daily drinking. Using a calendar to aid recall, participants retrospectively report their daily alcohol consumption over a specified period (e.g., the past 30 days). The data is used to calculate key metrics such as the number of drinking days, the number of heavy drinking days, and the average number of standard drinks consumed per day or per week. A higher value indicates a greater level of alcohol consumption. | baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months |
| From baseline to mid-treatment (Week 2) and end of treatment (Week 4) |
| Amplitude of Low-Frequency Fluctuations (ALFF) Measured by fMRI | The amplitude of low-frequency fluctuations (ALFF) will be calculated from resting-state fMRI data. It measures the intensity of spontaneous neural activity in specific brain regions. The value is typically presented as a normalized Z-score. A higher ALFF value indicates greater regional spontaneous neural activity. | From baseline to mid-treatment (Week 2) and end of treatment (Week 4) |
| ID | Term |
|---|---|
| D008108 | Liver Diseases, Alcoholic |
| D005234 | Fatty Liver |
| D024821 | Metabolic Syndrome |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D020751 | Alcohol-Induced Disorders |
| D019973 | Alcohol-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D007333 | Insulin Resistance |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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