Transcranial Electrical Stimulation for Comorbid Depression and Chronic Pain

Official title

Transcranial Electrical Stimulation for Comorbid Depression and Pain: From Technological Development to Clinical Translation in a Multicenter Trial

Overview

This clinical trial aims to investigate a novel non-pharmacological intervention, transcranial electrical stimulation (tES), for the treatment of comorbid depression and chronic pain. The primary objectives are to optimize neurostimulation parameters through a multicenter randomized controlled design and to elucidate the underlying neural circuit-immune interaction mechanisms of this comorbidity. Participants with comorbid depression and chronic pain will be randomly assigned to receive one of four interventions: (1) anodal tDCS unilateral hemispheric concurrent dual-site stimulation (a-tDCS UHCDS) targeting the left DLPFC and M1; (2) single-target anodal tDCS over the left DLPFC; (3) 40 Hz gamma transcranial alternating current stimulation (tACS); or (4) sham stimulation. The intervention period will last for 2 weeks, followed by a series of post-treatment follow-up assessments. Researchers will compare the changes in depression severity (e.g., assessed by HAMD-17) and pain intensity (e.g., NRS, BPI) across groups to evaluate the efficacy. Secondary outcomes include pain perception, quantitative sensory testing (QST), fMRI, MEG, metabolic markers, neurotransmitter and inflammatory biomarkers. This study aims to provide a precise, individualized therapeutic strategy, reduce reliance on pharmacotherapy, and promote the development of domestic high-end medical devices.

Interventions

• Device Dual-target a-tDCS UHCDS
  Participants receive active anodal transcranial direct current stimulation (tDCS) delivered via a unilateral hemispheric concurrent dual-site stimulation (UHCDS) montage. Two anodal electrodes (5 × 5 cm) are placed over the left dorsolateral prefrontal cortex (DLPFC, F3) and the left primary motor cortex (M1, C3), with a common cathodal reference electrode (5 × 7 cm) placed over the contralateral supraorbital area (Fp2). A constant current of 2 mA is applied for 20 minutes per session, with a 30
• Device Single-target a-tDCS
  Participants receive active single-target anodal transcranial direct current stimulation (tDCS). The anodal electrode (5 × 5 cm) is placed over the left dorsolateral prefrontal cortex (DLPFC, F3), and the cathodal electrode (5 × 7 cm) is placed over the contralateral supraorbital area (Fp2). A constant current of 2 mA is applied for 20 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).
• Device 10 Hz alpha-tACS
  Participants receive active 10 Hz transcranial alternating current stimulation (tACS). Three 5 × 5 cm electrodes are placed as follows: target electrode over F3, counter electrode over F4, and reference electrode over Cz. A sinusoidal alternating current at 10 Hz frequency (alpha band) is applied with the following intensity parameters: 1 mA (zero-to-peak) at F3 and F4 electrodes, and 2 mA (zero-to-peak) at the Cz reference electrode. Stimulation duration is 40 minutes per session, including 30-
• Device Sham tES
  Participants receive sham transcranial electrical stimulation (tES) using the same electrode montage as the corresponding active groups. 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. For the tACS sham condition, th

Primary outcome measures

• Brief Pain Inventory (BPI) - Pain Intensity Subscale [Time frame: Baseline, 1 week, 2 weeks, 6 weeks]

Secondary outcome measures (12)

• Hamilton Depression Rating Scale-17 (HAMD-17) - Mean Percentage Reduction from Baseline [Time frame: Baseline, 1 week, 2 weeks, 6 weeks]
• Quantitative Sensory Testing (QST) - Change from Baseline [Time frame: Baseline, 2 weeks]
• Pain Catastrophizing Scale (PCS) - Mean Percentage Reduction from Baseline [Time frame: Baseline, 1 week, 2 weeks, 6 weeks]
• Generalized Anxiety Disorder Scale-7 (GAD-7) - Mean Percentage Reduction from Baseline [Time frame: Baseline, 1 week, 2 weeks, 6 weeks]
• Pain Sensitivity Questionnaire (PSQ) - Percentage Reduction from Baseline [Time frame: Baseline, 1 week, 2 weeks, 6 weeks]
• Clinical Global Impression (CGI) - Change from Baseline [Time frame: Baseline, 1 week, 2 weeks, 6 weeks]
• Mini-Mental State Examination (MMSE) - Change from Baseline [Time frame: baseline, 1 week, 2 weeks, 6 weeks]
• Change from baseline Blood BDNF at 2 weeks, 6weeks [Time frame: Baseline, 2 weeks, 6weeks]
• Change from baseline Blood inflammatory factors at 2 weeks, 6weeks [Time frame: Baseline, 2 weeks, 6weeks]
• Change from baseline Blood lipid at 2 weeks, 6weeks [Time frame: Baseline, 2 weeks, 6weeks]
• Change from baseline Blood Glucose at 2 weeks, 6 weeks [Time frame: Baseline, 2 weeks, 6 weeks]
• Change from baseline fNIRS at 2 weeks and 6 weeks [Time frame: Baseline, 2 weeks, 6 weeks]

Eligibility criteria

Inclusion criteria

• Aged 18-65 years;
• Meet the diagnostic criteria for a depressive episode according to DSM-5, with current mild-to-moderate depressive symptoms (HAMD-17 score ≥8 and ≤23);
• Report persistent pain lasting ≥3 months and score ≥4 on item 5 of the Brief Pain Inventory (BPI);
• Maintain a stable anti-depression drug and psychological treatment plan (including dosage, drug type, or therapeutic approach) for at least four weeks prior to enrollment;
• Right-handed, with normal hearing, vision, or corrected vision;
• Able to voluntarily provide written informed consent to participate in the study and willing and capable of complying with all study procedures.

Exclusion criteria

• Diagnosed with other psychiatric disorders, including schizophrenia spectrum disorders, bipolar I disorder (due to potential risk of manic episodes and contraindication of lithium or anticonvulsants), primary anxiety disorders, depression associated with severe somatic illness, etc.
• Active suicidal ideation, defined as a score of 4 on item 3 of the HAMD-17.
• Severe or treatment-resistant depression (HAMD-17 score ≥23, with current depressive episode lasting at least 2 years or failure to respond to two or more antidepressant treatments during the current episode).
• Substance use disorder within the past 3 months.
• Experience of malignant pain due to cancer pain syndrome, visceral pain (e.g., gastric pain), or referred pain (e.g., back pain from pancreatitis).
• Neurological disorders associated with structural brain abnormalities (e.g., traumatic brain injury, recent stroke, brain tumor).
• Having undergone neuromodulation treatments within the past 3 months, including electroconvulsive therapy (MECT), repetitive transcranial magnetic stimulation (rTMS), or transcranial electrical stimulation (tES).
• Contraindications to transcranial electrical stimulation (e.g., intracranial metal implants, cardiac pacemaker, cochlear implant, skin lesions at stimulation sites, personal or family history of epilepsy).
• Current or within the past 1 month use of medications affecting central nervous system excitability or pain, such as anticonvulsants, lithium, opioids, nonsteroidal anti-inflammatory drugs, and antipsychotics. Occasional as-needed use of acetaminophen as rescue medication is permitted but must be documented in detail in the study diary.
• Signs of dementia or other severe cognitive impairment (MMSE score <24).
• Severe or unstable somatic diseases, including but not limited to: neurological disorders (e.g., epilepsy, stroke, migraine, history of cranial surgery); cardiovascular diseases (e.g., uncontrolled hypertension, heart failure, arrhythmia, myocardial infarction); respiratory disorders (e.g., severe sleep apnea syndrome); malignancy or immunocompromised status; uncontrolled diabetes (fasting blood glucose >12 mmol/L).
• Pregnancy or lactation.
• Concurrent participation in another clinical trial, participation in any clinical trial within the past 90 days, or planned participation in another trial during the study period.
• Any contraindications to magnetic resonance imaging (e.g., metal implants, claustrophobia, respiratory or motor impairments).
• Inability to cooperate with study assessments.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 2 centers

• Shanghai Mental Health Center — Shanghai
• Shanghai Tenth People's Hospital — Shanghai

Identifiers

NCT: NCT07334561 · 2025-80

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗