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) and generalized anxiety disorder (GAD).

All participants will be enrolled as two independent cohorts and randomized separately within each diagnostic group. 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. Participants with generalized anxiety disorder will be randomized to receive high-frequency TI-tACS(80Hz), low-frequency TI-tACS(5Hz), 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 the MDD cohort is the change from baseline in the Hamilton Depression Rating Scale (HAMD-17) at week 2. The primary outcome for the GAD cohort is the change from baseline in the Hamilton Anxiety Rating Scale (HAMA) at week 2. Secondary outcomes include changes in clinical symptoms, cognitive function, and safety profiles in both the MDD and GAD cohorts.

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are highly prevalent psychiatric disorders 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 or GAD. Participants with either disorders will be enrolled as independent cohorts and randomized separately within each diagnostic group to receive active or sham TI-tACS according to the study protocol.

Approximately 192 participants (102 with MDD and 90 with GAD) 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) or Generalized Anxiety Disorder (GAD) according to DSM-5 criteria, assessed by trained researchers using the Structured Clinical Interview for DSM-5 (SCID), without psychotic features;
3. For MDD participants: HAMD-17 score ≥14; inadequate response to stable, regular antidepressant medication for at least 1 month at an adequate dose;
4. For GAD participants: HAMA score ≥14; stable, regular medication for at least 2 months;
5. Education level: junior high school or above; adequate cognitive and language ability to understand and complete study assessments;
6. 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 or GAD;
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.

Individual participant data will not be shared because the dataset includes sensitive neuroimaging and biological data that may compromise participant confidentiality.

This study is conducted using a double-blind design. Participants and outcome assessors are blinded to group assignment. Randomization codes are generated and maintained by an independent researcher who is not involved in participant assessment or data analysis. Participants assigned to the active stimulation groups receive temporal interference transcranial alternating current stimulation with different stimulation frequencies targeting the right amygdala. Participants in the sham stimulation group undergo identical electrode placement and stimulation procedures. In the sham condition, the stimulation current is ramped up for 15 seconds and then discontinued, followed by a 15-second ramp-down after 20 minutes, without delivering effective stimulation. The stimulation setup, procedures, and device appearance are identical across groups to maintain blinding.