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:
* Can rTMS effectively treat MetALD? * Is an individualized, precision-targeted rTMS approach more effective than the standard rTMS method? * What changes in brain activity are associated with the treatment?
Researchers will compare three different types of stimulation:
* Group A: Individualized rTMS targeting a deep brain reward area (the Nucleus Accumbens) based on each participant's brain scan (fMRI). * Group B: Standard rTMS applied using the traditional "5 cm" rule for positioning. * Group C: Sham (placebo) rTMS, which mimics the procedure but delivers no significant magnetic stimulation.
Participants will:
* Be randomly assigned to one of the three groups (A, B, or C). * Undergo an MRI brain scan before starting treatment. * Receive a total of 20 rTMS sessions, completing at least 4 sessions per week. * Have additional MRI scans and clinical assessments halfway through and immediately after the treatment course. * Attend follow-up visits at 1, 3, and 6 months after treatment completion to assess long-term effects.
Participants are able to understand the study protocol, requirements, and restrictions, are fully informed of potential adverse events, are willing to comply with follow-up visits, and voluntarily sign the informed consent form before enrollment.
Meet the diagnostic criteria for MASLD according to the Guidelines for the Prevention and Treatment of Metabolic (Non-Alcoholic) Fatty Liver Disease (2024 Edition), and fulfill the European definition of MetALD with moderate alcohol consumption (20-50 g/day for women; 30-60 g/day for men).
Age between 18 and 65 years.
Body mass index (BMI) > 24 kg/m².
Contraindications to magnetic resonance imaging (MRI) or transcranial magnetic stimulation (TMS).
Mild cognitive impairment, defined as Montreal Cognitive Assessment (MoCA) score < 25.
Severe comorbid somatic diseases or neurological disorders.
History of psychiatric disorders, or current use of antipsychotic medications.
Parallel
Individually Targeted rTMS
DeviceParticipants 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.
Conventional rTMS
DeviceConventional 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.
Transcranial Magnetic Stimulation Sham
DeviceSham 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).
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)
Change in Controlled Attenuation Parameter (CAP, dB/m) From Baseline as Assessed by Vibration-Controlled Transient Elastography (FibroScan® VCTE)
Change in Liver Stiffness Measurement (LSM, kPa) From Baseline as Assessed by FibroScan® VCTE
LFC From Baseline as Measured by MRI-PDFF
Proportion of Participants Achieving ≥30% or ≥50% Reduction in LFC From Baseline
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.
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.
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