The goal of this clinical trial is to learn if active transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) can improve pain symptoms in patients with major depressive disorder (MDD) and chronic pain symptoms. It will also explore the neural mechanisms underlying these potential effects. The main questions it aims to answer are:
1. Are there any differences in the overall efficacy among the three intervention groups (tACS, tDCS, and sham)?
2. Is active tACS superior to sham stimulation in reducing pain symptoms in patients with MDD and chronic pain over the 2-week treatment period and at the 6-week follow-up?
3. Is active tACS superior to active tDCS in reducing pain symptoms?
4. Does active tACS, compared to tDCS, demonstrate a more persistent improvement in pain symptoms, as measured at the 6-week follow-up?
5. As an exploratory objective, what neural oscillation entrainment mechanisms underlie the potential analgesic effects of tACS?
Researchers will compare three parallel groups: active tACS, active tDCS, and sham stimulation, to evaluate their efficacy. All three groups are randomized and double-blinded.
In addition, a separate exploratory open-label cohort of 10 participants will receive the same active tACS intervention while performing a cognitive task. This exploratory arm is designed to investigate the neural oscillation entrainment effects of tACS. Data from this arm will be analyzed separately and are not included in the primary confirmatory analyses.
Participants in the main randomized trial will:
1. Receive 40 minutes of stimulation (tACS, tDCS, or sham) once daily, 5 days per week, for 2 weeks (10 sessions total).
2. Complete clinical assessments and cognitive tests at baseline, mid-intervention (week 1), post-intervention (week 2), and at a 6-week follow-up.
3. Undergo resting-state functional MRI (rs-fMRI) and blood sample collection at baseline and post-intervention for exploratory biomarker analyses.
Participants in the exploratory open-label arm will:
1. Receive active tACS (1 mA, 10 Hz, 40 minutes) once daily, 5 days per week, for 2 weeks (10 sessions total), while performing a cognitive task during stimulation.
2. Complete resting-state and task-state EEG recordings at the following time points:
(1) At baseline (pre-intervention) (2) Immediately before and after the 1st tACS session (3) Immediately before and after the 10th tACS session (4) On the day after completion of all 10 sessions These EEG recordings are designed to assess: (1) the immediate entrainment effects of a single tACS session, (2) the cumulative effects after repeated tACS sessions, and (3) the persistent neural plasticity changes following the full intervention course.