Transcranial Electrical Stimulation for Comorbid Depression and Pain: From Technological Development to Clinical Translation in a Multicenter Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 160
- 试验地点
- 4
- 主要终点
- Proportion of Participants Achieving MCID on BPI Pain Intensity Subscale
研究概览
简要总结
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:
- Are there any differences in the overall efficacy among the three intervention groups (tACS, tDCS, and sham)?
- 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?
- Is active tACS superior to active tDCS in reducing pain symptoms?
- Does active tACS, compared to tDCS, demonstrate a more persistent improvement in pain symptoms, as measured at the 6-week follow-up?
- 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:
- Receive 40 minutes of stimulation (tACS, tDCS, or sham) once daily, 5 days per week, for 2 weeks (10 sessions total).
- Complete clinical assessments and cognitive tests at baseline, mid-intervention (week 1), post-intervention (week 2), and at a 6-week follow-up.
- 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:
- 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.
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Meets the diagnostic criteria for a depressive episode (DSM-5);
- •HAMD-17 score of ≥8 and ≤23 (mild-to-moderate depressive symptoms) based on the current assessment;
- •4 or higher on Item 5 of the Brief Pain Inventory (BPI), and persistent pain lasting more than three months;
- •Ages 18-80;
- •Right-handed, with normal hearing, vision, or corrected vision;
- •Have a high school education or higher and be able to understand and complete research-related assessments;
- •Maintain a consistent regimen of analgesic and antidepressant medications and psychotherapy (including dosage and type of medication or treatment method) for four weeks prior to enrollment;
- •The subject (or his or her legal representative, if applicable) signed an informed consent form stating that he or she understood the purpose and procedure of the trial and was willing to participate in it.
排除标准
- •Diagnosed according to the DSM-5 as meeting any of the following criteria: ① Major depressive disorder or treatment-resistant depression (HAMD-17 score ≥ 24, and the current episode has lasted ≥ 2 years, or the current episode has been unresponsive to treatment with ≥ 2 antidepressants); ② Schizophrenia spectrum disorder; ③ Bipolar I disorder; ④ Anxiety disorders (including generalized anxiety disorder, panic disorder, social anxiety disorder, etc.); ⑤ Depressive disorder caused by a medical condition.
- •Experiencing malignant pain caused by cancer pain syndrome, visceral pain (such as stomach pain), referred pain (such as back pain caused by pancreatitis), and so on;
- •Patients with severe or unstable physical illnesses, including but not limited to: neurological disorders (such as epilepsy, stroke, migraine, history of cranial surgery, etc.); neurological disorders accompanied by structural brain abnormalities (e.g., traumatic brain injury, recent stroke, brain tumor); cardiovascular diseases (e.g., uncontrolled hypertension, heart failure, arrhythmias, myocardial infarction, etc.); respiratory diseases (e.g., severe sleep apnea syndrome); malignant tumors or immunodeficiency; uncontrolled diabetes (fasting blood glucose > 12 mmol/L);
- •Excessive alcohol consumption within 30 days prior to the start of the trial, or a history of alcohol or drug dependence within the past 6 months;
- •Women who are pregnant, breastfeeding, or planning to become pregnant within 3 months of the start of the trial;
- •Currently taking medications that affect cortical excitability (e.g., benzodiazepines, antiepileptic drugs);
- •Have undergone neurostimulation therapy within the past 3 months, including electroconvulsive therapy (MECT), repetitive transcranial magnetic stimulation (rTMS), or transcranial electrical stimulation (tES);
- •Suffers from claustrophobia and is unable to undergo an fMRI scan (applies to subjects who require a functional MRI scan);
- •Contraindications to transcranial electrical stimulation (such as intracranial metal implants, pacemakers, cochlear implants, skin abrasions at the stimulation site, or a personal or family history of epilepsy, etc.);
- •Currently participating in another clinical trial, has participated in a clinical trial within the past 90 days, or plans to participate in another clinical trial during the study;
- •Participants with obvious suicidal tendencies, impulsive behavior, or an inability to cooperate with study evaluators;
- •Accompanied by psychotic symptoms;
- •Researchers believe there are other circumstances that make a participant unsuitable for the trial;
- •Patients with severe cognitive impairment (MMSE ≤ 17) were excluded;
- •Participants who are unable to cooperate with the study;
- •Those who voluntarily withdrew midway.
研究组 & 干预措施
tDCS
Participants receive active tDCS. The anodal electrode is placed over the left dorsolateral prefrontal cortex (F3), and the cathodal electrode 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).
干预措施: tDCS (Device)
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).
干预措施: alpha-tACS (Device)
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.
干预措施: Sham (Device)
Exploratory Open-Label tACS Group
Participants in this exploratory arm receive the same active tACS intervention as Arm alpha-tACS, with identical stimulation parameters (e.g., 1 mA, 40 minutes, 10 Hz, targeting the bilateral dorsolateral prefrontal cortex (DLPFC)). This arm is open-label (unblinded): participants and study personnel are aware of the treatment assignment. It serves as a supplementary exploratory cohort to explore preliminary neural oscillation entrainment effects of tACS. Unlike Arms 1-3, this arm is neither randomized nor blinded. Data from this arm will be analyzed separately and are not included in the primary confirmatory hypothesis testing of the randomized controlled trial. The overall study remains double-blind for the three-arm RCT component, with this exploratory arm conducted as an ancillary cohort.
干预措施: alpha-tACS (Device)
结局指标
主要结局
Proportion of Participants Achieving MCID on BPI Pain Intensity Subscale
时间窗: 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.
Brief Pain Inventory (BPI) - Pain Intensity Subscale
时间窗: Baseline, 1 week, 2 weeks, 6 weeks
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.
次要结局
- Percentage Reduction from Baseline in HAMD-17 Total Score(At 1 week (mid-intervention), 2 weeks (end of intervention), and 6 weeks (follow-up) post-baseline)
- Change from Baseline in HAMD-17 Total Score(At 1 week (mid-intervention), 2 weeks (post-intervention), and 6 weeks (follow-up))
- Change from Baseline in Pain Catastrophizing Scale (PCS) Total Score(At 1 week (mid-intervention), 2 weeks (end of intervention), and 6 weeks (follow-up) post-baseline)
- Change from Baseline in Generalized Anxiety Disorder Scale-7 (GAD-7) Total Score(At 1 week (mid-intervention), 2 weeks (end of intervention), and 6 weeks (follow-up) post-baseline)
- Change from Baseline in Clinical Global Impression (CGI) Total Score(At 1 week (mid-intervention), 2 weeks (post-intervention), and 6 weeks (follow-up))
- Change from Baseline in Resting-State Functional Connectivity of the DLPFC at 2 Weeks(Baseline and immediately after the 2-week intervention period)
- Change from baseline Blood BDNF at 2 weeks, 6weeks(Baseline, 2 weeks, 6weeks)
- Change from baseline Blood inflammatory factors at 2 weeks, 6weeks(Baseline, 2 weeks, 6weeks)
- Change from baseline Blood lipid at 2 weeks, 6weeks(Baseline, 2 weeks, 6weeks)
- Change from baseline Blood Glucose at 2 weeks, 6 weeks(Baseline, 2 weeks, 6 weeks)
- Hamilton Depression Rating Scale-17 (HAMD-17) - Mean Percentage Reduction from Baseline(Baseline, 1 week, 2 weeks, 6 weeks)
- Quantitative Sensory Testing (QST) - Change from Baseline(Baseline, 2 weeks)
- Pain Catastrophizing Scale (PCS) - Mean Percentage Reduction from Baseline(Baseline, 1 week, 2 weeks, 6 weeks)
- Generalized Anxiety Disorder Scale-7 (GAD-7) - Mean Percentage Reduction from Baseline(Baseline, 1 week, 2 weeks, 6 weeks)
- Pain Sensitivity Questionnaire (PSQ) - Percentage Reduction from Baseline(Baseline, 1 week, 2 weeks, 6 weeks)
- Clinical Global Impression (CGI) - Change from Baseline(Baseline, 1 week, 2 weeks, 6 weeks)
- Mini-Mental State Examination (MMSE) - Change from Baseline(baseline, 1 week, 2 weeks, 6 weeks)
- Change from baseline fNIRS at 2 weeks and 6 weeks(Baseline, 2 weeks, 6 weeks)
- Change from baseline MRI/rsfMRI at 2 weeks and 6weeks(Baseline, 2 weeks, 6weeks)
- Change from baseline EEG at 1 week, 2 weeks and 6 weeks(baseline, 1 week, 2 weeks and 6 weeks)