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.

Study Overview

• Status: Not yet recruiting
• Conditions: Major Depressive Disorder; Treatment-Resistant Major Depressive Disorder
• Intervention / Treatment: Device: Closed-loop Deep Brain Stimulation (DBS); Device: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active DBS; Participants will receive active closed-loop deep brain stimulation (DBS). After DBS implantation surgery, stimulation will be activated 7-14 days after surgery. Participants will receive closed-loop DBS treatment and undergo clinical follow-up assessments for 8 weeks to evaluate changes in depressive symptoms, cognitive function, and safety outcomes.	Device: Closed-loop Deep Brain Stimulation (DBS); Closed-loop deep brain stimulation (DBS) is an implanted neuromodulation intervention that delivers electrical stimulation based on real-time neural signals. Participants assigned to the DBS pathway will undergo implantation of a DBS system and receive either active or delayed stimulation according to the randomized study assignment. Clinical outcomes, cognitive function, brain activity, and safety outcomes will be assessed during follow-up.
Sham Comparator: Sham DB; Participants will receive sham deep brain stimulation (DBS) during the blinded comparison period. After DBS implantation surgery, stimulation will remain inactive until 8 weeks after surgery. Participants will undergo the same clinical follow-up assessments as the active DBS group during the study period.	Device: Closed-loop Deep Brain Stimulation (DBS); Closed-loop deep brain stimulation (DBS) is an implanted neuromodulation intervention that delivers electrical stimulation based on real-time neural signals. Participants assigned to the DBS pathway will undergo implantation of a DBS system and receive either active or delayed stimulation according to the randomized study assignment. Clinical outcomes, cognitive function, brain activity, and safety outcomes will be assessed during follow-up.
Experimental: Active taVNS; Participants will receive active transcutaneous auricular vagus nerve stimulation (taVNS). Electrical stimulation will be delivered through electrodes placed at the auricular stimulation sites. Participants will receive taVNS treatment and undergo clinical follow-up assessments for 8 weeks to evaluate changes in depressive symptoms, cognitive function, and safety outcomes.	Device: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS); Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation intervention that delivers electrical stimulation through electrodes placed on auricular sites associated with the vagus nerve. Participants assigned to the taVNS pathway will receive either active or sham stimulation according to the randomized study assignment. Clinical outcomes, cognitive function, brain activity, and safety outcomes will be assessed during follow-up.
Sham Comparator: Sham taVNS; Participants will receive sham transcutaneous auricular vagus nerve stimulation (taVNS). The electrodes will be placed at the same auricular sites as active stimulation, but no therapeutic electrical stimulation will be delivered. Participants will undergo the same clinical follow-up assessments as the active taVNS group.	Device: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS); Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation intervention that delivers electrical stimulation through electrodes placed on auricular sites associated with the vagus nerve. Participants assigned to the taVNS pathway will receive either active or sham stimulation according to the randomized study assignment. Clinical outcomes, cognitive function, brain activity, and safety outcomes will be assessed during follow-up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 17-item Hamilton Rating Scale for Depression (HAMD-17) score	The primary efficacy outcome is the change in the 17-item Hamilton Depression Rating Scale (HAMD-17) score from baseline to week 8 after intervention. The HAMD-17 is used to assess the severity of depressive symptoms, with higher scores indicating greater severity of depressive symptoms. A decrease in HAMD-17 score indicates improvement in depressive symptoms.	Baseline to Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hamilton Anxiety Rating Scale (HAMA) score	The change in Hamilton Anxiety Rating Scale (HAMA) score from baseline to Week 8 will be evaluated to assess changes in anxiety symptom severity. The HAMA total score ranges from 0 to 56, with higher scores indicating greater severity of anxiety symptoms. A decrease in HAMA score indicates improvement in anxiety symptoms.	Baseline to Week 8
Change in Montreal Cognitive Assessment scale (MoCA) score	The change in Montreal Cognitive Assessment (MoCA) score from baseline to Week 8 will be evaluated to assess changes in cognitive function. The MoCA total score ranges from 0 to 30, with higher scores indicating better cognitive function. An increase in MoCA score indicates improvement in cognitive function.	Baseline to Week 8
Change in Montgomery-Asberg Depression Rating Scale (MADRS) score	The change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to Week 8 will be evaluated to assess changes in depressive symptom severity. The MADRS total score ranges from 0 to 60, with higher scores indicating greater severity of depressive symptoms. A decrease in MADRS score indicates improvement in depressive symptoms.	Baseline to Week 8
Change in Patient Health Questionnaire-9 (PHQ-9) score	The change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to Week 8 will be evaluated to assess changes in depressive symptoms. The PHQ-9 total score ranges from 0 to 27, with higher scores indicating greater severity of depressive symptoms. A decrease in PHQ-9 score indicates improvement in depressive symptoms.	Baseline to Week 8
Change in Generalized Anxiety Disorder-7 (GAD-7) score	The change in Generalized Anxiety Disorder-7 (GAD-7) score from baseline to Week 8 will be evaluated to assess changes in anxiety symptoms. The GAD-7 total score ranges from 0 to 21, with higher scores indicating greater severity of anxiety symptoms. A decrease in GAD-7 score indicates improvement in anxiety symptoms.	Baseline to Week 8
Change in Clinical Global Impression-Improvement (CGI) score, using Clinical Global Impression-Severity (CGI-S)	The change in Clinical Global Impression-Severity (CGI-S) score from baseline to each follow-up assessment will be evaluated to assess changes in overall illness severity. The CGI-S is rated on a 7-point scale from 1 to 7, with higher scores indicating greater illness severity. A decrease in CGI-S score indicates improvement in overall illness severity.	Baseline to Week 8
Change in Clinical Global Impression-Improvement (CGI) score, using Clinical Global Impression-Improvement (CGI-I).	The Clinical Global Impression-Improvement (CGI-I) score will be used to assess overall clinical improvement relative to baseline. The CGI-I is rated on a 7-point scale from 1 to 7, with 1 indicating very much improved, 4 indicating no change, and 7 indicating very much worse. Lower scores indicate greater clinical improvement.	Baseline to Week 8
Change in Personal and Social Performance Scale (PSP) score	The change in Personal and Social Performance (PSP) Scale score from baseline to each follow-up assessment will be evaluated to assess changes in personal and social functioning. The PSP total score ranges from 1 to 100, with higher scores indicating better personal and social functioning. An increase in PSP score indicates improvement in personal and social functioning.	Baseline to Weeks 1, 2, 4, 6, and 8
Change in Social Functioning Rating Scale (SFRS) score	The change in Social Functioning Rating Scale (SFRS) score from baseline to Week 8 will be evaluated to assess changes in social functioning. The SFRS consists of 36 items, with each item scored from 0 to 7, resulting in a total score ranging from 0 to 252. Higher scores indicate poorer social functioning. A decrease in SFRS score indicates improvement in social functioning.	Baseline to Week 8
EEG Delta, Theta, Alpha, and Beta Band Power and Theta/Beta Power Ratio	EEG recordings will be analyzed to quantify changes in spectral power across predefined frequency bands, including delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz) bands, and theta/beta power ratio from baseline to week 8.	Baseline to Week 8
Changes in neuroimaging measures assessed by magnetic resonance imaging (MRI)		Baseline to Week 8
Number and percentage of participants with adverse events or serious adverse events	Adverse events will be assessed throughout the study period. Clinically significant findings from laboratory tests, vital signs, electrocardiography, and other examinations will be recorded as adverse events when considered clinically significant by the investigator. When a specific clinical diagnosis can be made, the diagnosis will be recorded as the adverse event; when no specific diagnosis can be made, the clinical significance will be determined by the investigator. Adverse events will be classified as mild, moderate, or severe, and their occurrence time, severity, duration, management, and outcome will be recorded. The number and percentage of participants experiencing adverse events will be summarized.	Baseline to Week 8

Collaborators and Investigators

• Sponsor: Shanghai Mental Health Center
• Collaborators: Xuanwu Hospital, Beijing; Anding Hospital, Beijing

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: August 14, 2026
• First Submitted That Met QC Criteria: August 24, 2026
• First Posted (Actual): August 25, 2026

Study Record Updates

• Last Update Posted (Actual): August 28, 2026
• Last Update Submitted That Met QC Criteria: August 27, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 2026-63

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No