Precision Closed-loop Brain-Computer Interface Neuromodulation for Treatment-Resistant Depression

Multi-scenario Clinical Application of Precision Closed-loop Brain-Computer Interface Neuromodulation in Treatment-Resistant Major Depressive Disorder

The goal of this clinical trial is to evaluate whether precision closed-loop neuromodulation treatments can improve depressive symptoms and daily functioning in people with treatment-resistant major depressive disorder (TRD). The study will assess the effectiveness and safety of two neuromodulation approaches: closed-loop deep brain stimulation (DBS) and transcutaneous auricular vagus nerve stimulation (taVNS).

Treatment-resistant major depressive disorder refers to depression that does not improve sufficiently after adequate treatment with standard antidepressant therapies. This study focuses on people with TRD, including individuals with early-onset depression, a history of self-harm or suicidal thoughts, or depression associated with traumatic experiences.

This study aims to answer whether closed-loop DBS and taVNS can reduce depressive symptoms compared with sham stimulation, whether these treatments are safe and well tolerated, and whether changes in brain activity are associated with clinical improvement.

This is a multicenter, prospective clinical study conducted at Shanghai Mental Health Center, Beijing Anding Hospital, and Xuanwu Hospital. Eligible participants with TRD will receive either DBS or taVNS according to patient preference. Within each intervention group, participants will be randomly assigned to active stimulation or sham stimulation groups to assess treatment effects.

During the study, participants will receive neuromodulation treatment and complete regular follow-up assessments. These assessments will include evaluation of depressive symptoms, anxiety symptoms, cognitive function, social functioning, brain electrical activity using electroencephalography (EEG), brain imaging using magnetic resonance imaging (MRI), and monitoring of adverse events.

The study will compare changes in clinical symptoms, brain-related measures, and safety outcomes between active and sham stimulation groups. The findings may help determine whether precision neuromodulation approaches can provide a new treatment option for people with treatment-resistant major depressive disorder.

Inclusion Criteria:

• Age 18 to 70 years, regardless of sex.

• At least primary school education and able to understand the content of the assessment scales.

• Meet the diagnostic criteria for depressive disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

• Have a history of depression lasting at least 24 months and have received adequate-dose and adequate-duration treatment with at least 2 antidepressants for 8 weeks or longer, including electroconvulsive therapy without anesthesia, with a reduction rate in the HAMD-17 score of 20% or less after treatment.

• Have a HAMD-17 score greater than 17 at baseline.

• Have been on a stable regimen of the current antidepressant medication for at least 1 month before enrollment.

• Meet at least one of the following three criteria:

  1. Depression with onset before 18 years of age.

     1. The age at first depressive episode was younger than 18 years, confirmed by a psychiatrist at the attending physician level or above according to the DSM-5 or International Classification of Diseases, 11th Revision (ICD-11) diagnostic criteria for depressive disorders.
     2. The age at onset can be supported by at least one of the following sources: the participant's medical history report, previous medical records, or information about age at onset provided by a guardian.
     3. If the onset age is unclear, confirmation requires consistency between at least two independent sources of information.

  2. A clear history of self-injurious or suicidal behavior:

     1. As confirmed by a guardian or through review of previous medical records, the participant has had clinically significant self-injurious behavior, such as cutting, burning, hitting oneself, involving intentional self-harm without the intent to die; or suicidal behavior or tendencies, such as recurrent suicidal ideation, suicidal planning, or a suicide attempt.
     2. Such behavior or tendencies must be documented in, but not limited to, outpatient or inpatient medical records, psychological assessment records, or school or community referral records. Alternatively, they may be clearly described by a guardian and documented and confirmed in writing by the investigator.

  3. A clear history of traumatic stress:

     1. As confirmed by a guardian or through review of previous medical records, before the onset or worsening of depression, the participant experienced a situation meeting the DSM-5 definition of traumatic events, including but not limited to: actual or threatened death; serious injury; sexual violence; abuse; neglect; bullying; major accidents; war; natural disasters; intimate partner violence.
     2. The traumatic event must have a clearly documented time of occurrence, type of event, and temporal relationship with the onset or worsening of depressive symptoms.
     3. Standardized instruments such as life event questionnaires may be used as supplementary assessments. However, final eligibility determination must be made by the investigator based on comprehensive evaluation of: information provided by the legal guardian; previous medical records; clinical judgment.

• Participants or their legal guardians must voluntarily sign the informed consent form and must be capable of completing follow-up assessments;

• Participants assigned to the DBS group must pass preoperative evaluation for DBS surgery and must have no contraindications for neurosurgical procedures;

• Participants assigned to the taVNS group must pass taVNS eligibility assessment, including: no recent facial or auricular injuries; no metallic implants in the head or heart; no active gastrointestinal symptoms; no acute exacerbation of respiratory disorders; no personal or family history of epilepsy; no frequent or severe headaches.

Exclusion Criteria:

• Previous diagnosis of: schizophrenia; schizoaffective disorder; substance dependence or drug addiction; mental disorders secondary to other medical conditions; or presence of significant psychotic symptoms, including delusions and hallucinations.

• Presence of severe or unstable disorders involving the: central nervous system; cardiovascular system; respiratory system; liver; kidney; endocrine system; hematological system; or other major organ systems, which, in the investigator's judgment, make the participant unsuitable for enrollment.

• Female participants who are: pregnant; breastfeeding; planning pregnancy during the study period or within 8 weeks after the last medication administration; or male participants with plans for reproduction during the study period.

• Participation in another clinical trial within the previous 3 months.

• Inability to undergo MRI examination.

• MRI findings indicating any of the following: more than two lacunar infarcts; regional infarction lesions with a volume >1 cm³; significant white matter lesions; a total Fazekas score of 3.

• Severe aphasia, visual impairment, hearing impairment, or other conditions preventing completion of study procedures.

• Any condition that, in the investigator's opinion, makes the participant unsuitable for participation in this study.

• Contraindications to DBS surgery or chronic vagus nerve stimulation (VNS).

• High suicide risk determined using the Columbia-Suicide Severity Rating Scale (C-SSRS). Participants will be excluded if any of the following criteria are met:

  1. A suicide attempt within the previous 3 months;
  2. Persistent active suicidal ideation with intent to act, as indicated by the C-SSRS assessment;
  3. Emergency department visit or hospitalization due to suicide risk within 1 month prior to enrollment;
  4. Baseline C-SSRS assessment indicates non-persistent active suicidal ideation, but the investigator determines, based on the intensity of suicidal intent score (C-SSRS Item 5) and clinical evaluation, that the participant has severely impaired impulse control and immediate suicide risk, confirmed by a psychiatric specialist.