Temporal Interference Transcranial Alternating Current Stimulation for Major Depressive Disorder

A Double-Blind, Randomized, Sham-Controlled Clinical Trial of Temporal Interference Transcranial Alternating Current Stimulation for the Treatment of Major Depressive Disorder

This multi-center, double-blind study, randomized controlled trial aims to evaluate the efficacy and safety of Temporal Interference transcranial Alternating Current Stimulation (TI-tACS) in patients with major depressive disorder (MDD)

Participants with major depressive disorder will be randomized to receive high-frequency TI-tACS(130 Hz), low-frequency TI-tACS(2Hz), or sham stimulation targeting the right amygdala.

The intervention consists of 20 stimulation sessions administered over 2 weeks (twice a day for 5 consecutive days, followed by a 2-day break, and another 5 consecutive days). Clinical assessments will be conducted at baseline, during treatment, and at multiple follow-up time points up to 6 months.

The primary outcome for MDD is the change from baseline in the Hamilton Depression Rating Scale (HAMD-17) at week 2. Secondary outcomes include changes in clinical symptoms, cognitive function, and safety profiles.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder associated with substantial disability and impaired quality of life. Neuroimaging studies have demonstrated abnormalities in distributed cortical-subcortical circuits, particularly involving the amygdala, which plays a central role in emotional processing and symptom regulation. Although several neuromodulation techniques have shown therapeutic potential, currently available approaches have limited ability to selectively modulate deep brain structures without invasive procedures.

Temporal interference transcranial alternating current stimulation (TI-tACS) is a novel non-invasive neuromodulation technique that delivers two high-frequency alternating currents with slightly different frequencies to generate a low-frequency envelope within deep brain regions. This approach enables selective modulation of deep neural structures, such as the amygdala, while minimizing stimulation of the overlying cortex.

This is a multicenter, randomized, triple-blind, sham-controlled clinical trial designed to evaluate the efficacy, safety, and neurobiological mechanisms of TI-tACS in participants with MDD. Participants will be enrolled randomized to receive active or sham TI-tACS according to the study protocol.

Approximately 102 participants will be recruited. Following written informed consent, participants will undergo baseline assessments and subsequent study evaluations according to the protocol. Study assessments include clinical evaluations, neurocognitive testing, electroencephalography (EEG), magnetic resonance imaging (MRI), and biological sample collection. TI-tACS treatment consists of 20 stimulation sessions administered over two weeks (two sessions per day for five consecutive days, followed by a two-day break, and another five consecutive treatment days).

Participants will also complete scheduled post-treatment follow-up assessments to evaluate the persistence of treatment effects and the long-term safety of TI-tACS.

Inclusion Criteria:

1. Age between 18 and 55 years (inclusive), any gender;
2. Diagnosis of a single or recurrent episode of Major Depressive Disorder (MDD) according to DSM-5 criteria, assessed by trained researchers using the Structured Clinical Interview for DSM-5 (SCID), without psychotic features;
3. HAMD-17 score ≥14; inadequate response to stable, regular antidepressant medication for at least 1 month at an adequate dose;
4. Education level: junior high school or above; adequate cognitive and language ability to understand and complete study assessments;
5. Voluntary participation with signed informed consent; ability to comply with study visits, treatment schedules, laboratory tests, and other study procedures.

Exclusion Criteria:

1. History of psychiatric disorders other than MDD;
2. Pregnancy or lactation;
3. Neurologic disorders or serious systemic diseases (e.g., thyroid disease, lupus erythematosus, diabetes, hepatic or renal impairment, active infection, major trauma);
4. History of significant head injury or coma
5. Receipt of physical therapies such as electroconvulsive therapy or rTMS within the past six months before enrollment
6. Suspected or confirmed history of alcohol or substance dependence;
7. Current severe suicidal ideation or recent suicide attempt;
8. Current participation in another clinical trial or recent use of prohibited psychotropic medications;
9. Positive urine drug screening or abnormal thyroid function tests;
10. Contraindications to magnetic resonance imaging (MRI) or electroencephalography (EEG);
11. Inability to provide fully informed consent.