This randomized, sham-controlled clinical trial aims to evaluate the efficacy and safety of amygdala-targeted transcranial temporal interference stimulation (tTIS) in adults with major depressive disorder (MDD) and to explore its potential neurobiological mechanisms.
The main questions this study aims to answer are:
Whether active amygdala-targeted tTIS reduces depressive symptoms compared with sham stimulation.
Whether tTIS produces changes in amygdala-related neural activity and functional brain networks that are associated with clinical improvement.
Participants will be randomly assigned to receive either active tTIS or sham stimulation. They will complete a course of stimulation sessions and undergo clinical assessments before and after the intervention. Neuroimaging assessments will also be performed to investigate treatment-related changes in the amygdala and associated brain networks.
Aged 18 to 55 years, inclusive, with no restriction on sex.
Diagnosed with Major Depressive Disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), as determined by a study physician.
A 17-item Hamilton Depression Rating Scale (HAMD-17) score ≥17 at screening/baseline.
The antidepressant medication regimen must remain stable from at least 30 days before signing the informed consent form through the study period.
A history of other psychiatric disorders, neurological disorders, or substance abuse that, in the investigator's judgment, may interfere with the assessment of treatment efficacy.
A history of epilepsy, seizures, or convulsive episodes.
Presence of intracranial metallic foreign bodies or metallic implants in or near the heart.
Presence of organic brain disease, or a history of severe head injury or cranial surgery.
Parallel
Transcranial Temporal Interference Stimulation
DeviceActive transcranial temporal interference stimulation (tTIS) will be delivered using two pairs of scalp electrodes. Two high-frequency alternating currents with slightly different carrier frequencies will be applied to generate a low-frequency temporal interference envelope within the targeted amygdala region. Electrode placement and stimulation parameters will be determined according to the study protocol and individualized electric-field modeling when applicable. Participants assigned to the active group will receive 10 stimulation sessions, with each session lasting 30 minutes, according to the predefined treatment schedule.
Sham Transcranial Temporal Interference Stimulation
DeviceParticipants assigned to the sham group will undergo the same electrode placement and treatment procedures as the active stimulation group. Sham stimulation will include brief ramp-up and ramp-down periods to mimic the initial sensory experience of active stimulation, without delivering continuous therapeutic stimulation during the remainder of the session.
Change in 17-item Hamilton Depression Rating Scale (HAMD-17) Total Score
The 17-item Hamilton Depression Rating Scale (HAMD-17) is a clinician-rated scale used to assess the severity of depressive symptoms. Total scores range from 0 to 52, with higher scores indicating greater depressive symptom severity. The primary outcome is the change in HAMD-17 total score from baseline to the end of the 10-session intervention.
Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score
The Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-rated scale used to assess the severity of depressive symptoms. Total scores range from 0 to 60, with higher scores indicating greater depressive symptom severity. Changes in MADRS total score from baseline will be assessed following treatment and during follow-up.
Change in 17-item Hamilton Depression Rating Scale (HAMD-17) Total Score Across Treatment and Follow-up
Change in Hamilton Anxiety Rating Scale (HAMA) Total Score
The Hamilton Anxiety Rating Scale (HAMA) is a clinician-rated scale used to assess the severity of anxiety symptoms. Total scores range from 0 to 56, with higher scores indicating greater anxiety severity. Changes in HAMA total score from baseline will be assessed following treatment and during follow-up.
Change in Snaith-Hamilton Pleasure Scale (SHAPS) Score
The Snaith-Hamilton Pleasure Scale (SHAPS) is used to assess anhedonia and reduced capacity to experience pleasure. Changes in SHAPS score from baseline will be used to evaluate treatment-related changes in hedonic functioning.
DTI
Diffusion tensor imaging (DTI) will be used to explore treatment-related changes in white matter microstructural measures within neural pathways associated with the amygdala and emotion-regulation networks.
fMRI
Functional magnetic resonance imaging (fMRI) will be used to assess treatment-related changes in functional connectivity involving the amygdala and brain regions associated with emotional processing and regulation. Amygdala-based functional connectivity measures will be compared across study time points.
Incidence of Treatment-Emergent Adverse Events
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