Temporal Interference Transcranial Alternating Current Stimulation for Major Depressive Disorder

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.