Transcranial Electrical Stimulation for Comorbid Depression and Chronic Pain

Condition(s) studied

Investigational drug(s) / intervention(s)

tDCS: Participants receive active tDCS. The anodal electrode (5 × 5 cm) is placed over the left dorsolateral prefrontal cortex (F3), and the cathodal electrode (5 × 7 cm) is placed over the right dorsolateral prefrontal cortex (F4). A constant current of 2 mA is applied for 40 minutes per session, with a 30-second ramp-up and ramp-down period. The intervention is administered once daily for 2 weeks (total of 10 sessions).

alpha-tACS: Participants receive active alpha-tACS. Two electrodes are placed over F3 and F4. A sinusoidal alternating current at 10 Hz frequency (alpha band) is applied 1 mA (zero-to-peak) at the F3 and F4 electrodes. Stimulation duration is 40 minutes per session, including 30-second ramp-up and ramp-down periods. The intervention is administered once daily, 5 days per week, for 2 weeks (total of 10 sessions).

Sham: Sham group using the same electrode montage at F3/F4. To maintain blinding, the stimulator delivers current only during the initial 30-second ramp-up period, followed by an immediate ramp-down, and a final 30-second ramp-up at the end of the stimulation session. This mimics the initial sensation of active stimulation without delivering sufficient current to induce neural modulation.

Study summary

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.

Eligibility

Primary outcome measure(s)

• Proportion of Participants Achieving MCID on BPI Pain Intensity Subscale — At 1 week (mid-intervention), 2 weeks (end of intervention), and 6 weeks (follow-up) post-baseline
  Description: The BPI is a validated self-administered questionnaire that assesses the severity of pain and its impact on daily functioning. The pain intensity subscale consists of four items rating pain at its "worst," "least," "average," and "current" (right now). Each item is rated on a 0 to 10 numeric rating scale. Higher scores mean a worse outcome. The Minimal Clinically Important Difference (MCID) is defined as a reduction of ≥ 1 point from baseline in the BPI pain intensity score. The outcome is the proportion of participants in each group who achieve this MCID threshold at each follow-up time point.

Trial sites (2)

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