The goal of this clinical trial is to learn whether transcranial temporal interference stimulation (tTIS) can help treat major depressive disorder (MDD) in adults. The study will also learn about the safety of tTIS and explore how it may affect brain structure and brain function.

The main questions it aims to answer are whether active tTIS lowers depression symptom scores more than sham stimulation after treatment, and what medical problems or side effects participants have during or after tTIS.

Researchers will compare active tTIS targeting the left anterior limb of the internal capsule, active tTIS targeting the left subgenual anterior cingulate cortex, and sham stimulation. Sham stimulation is designed to feel similar to real stimulation but does not provide the same active treatment.

Participants with MDD will be randomly assigned to one of the three groups. They will receive two 20-minute treatment sessions each day for 5 days. They will complete depression, anxiety, pleasure, psychosomatic symptom, and safety assessments before treatment, after treatment, and during follow-up. They will also have brain magnetic resonance imaging scans before and after treatment.

Major depressive disorder (MDD) is a common and disabling mental disorder. Although medication, psychotherapy, and established brain stimulation methods can help many people with MDD, some participants still have insufficient improvement. Transcranial temporal interference stimulation (tTIS) is a non-invasive brain stimulation technique that may allow modulation of deeper brain regions or pathways. This study is designed to evaluate whether tTIS can improve depressive symptoms in adults with MDD, assess its safety, and explore potential neuroimaging mechanisms.

This is a single-center, randomized, double-blind, sham-controlled clinical trial conducted at Zhongda Hospital, Southeast University. Eligible participants with MDD will be randomly assigned in a 1:1:1 ratio to one of three groups: active tTIS targeting the left anterior limb of the internal capsule (ALIC), active tTIS targeting the left subgenual anterior cingulate cortex (sgACC), or sham tTIS. The sham stimulation will be designed to provide sensory feedback similar to active stimulation while maintaining blinding.

Participants with MDD will receive 10 treatment sessions over 5 consecutive days, with two 20-minute sessions each day. Clinical symptoms and safety will be assessed at baseline, after treatment, and during follow-up. The main clinical outcome is the change in the 24-item Hamilton Depression Rating Scale (HAMD-24) total score from baseline to after treatment. Secondary outcomes include follow-up changes in depressive symptoms, response and remission rates, anxiety symptoms, anhedonia, psychosomatic symptoms, side effects, and adverse events.

Multimodal 5.0T brain magnetic resonance imaging (MRI) will be collected from participants with MDD before and after treatment. MRI measures will include structural imaging, resting-state functional imaging, and diffusion imaging. These data will be used to explore changes in brain structure, functional connectivity, and diffusion-related measures after tTIS, and to identify potential imaging biomarkers related to treatment response.

Inclusion Criteria:

• Diagnosed with major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), by two independent psychiatrists
• 24-item Hamilton Depression Rating Scale (HAMD-24) total score greater than 20 at baseline
• Aged 18 to 65 years
• Right-handed
• Able to understand the study procedures and willing to provide written informed consent

Exclusion Criteria:

• History of epilepsy, brain tumor, or brain trauma
• Receipt of transcranial magnetic stimulation, transcranial electrical stimulation, or electroconvulsive therapy within the past 3 months
• Presence of metal implants or other contraindications to transcranial electrical stimulation or magnetic resonance imaging
• Acute or severe suicidal ideation
• Any other condition judged by the investigators to make participation unsuitable for this study

Individual participant data will not be publicly shared because the study involves sensitive mental health information and neuroimaging data. Data sharing may increase the risk of participant identification. De-identified data may be made available from the principal investigator upon reasonable request and with approval from the ethics committee, when permitted by applicable regulations and the informed consent.

Participants, treatment operators, and outcome assessors will be masked to group allocation. Eligible participants with major depressive disorder will be randomly assigned to active tTIS targeting the left anterior limb of the internal capsule, active tTIS targeting the left subgenual anterior cingulate cortex, or sham tTIS according to a computer-generated randomization table. Active and sham stimulation will be delivered using the same type of device, and sham stimulation will be designed to provide sensory feedback similar to active stimulation. Clinical outcome assessments will be performed by trained assessors who are not involved in treatment delivery and are unaware of the assigned intervention.