Cardiac Autonomic and Anxiety Regulation Via Closed-loop nEurofeedback in Recurrent Pregnancy Loss

NCT07325370 | Recruiting DMC

• 1 other identifier: CARE-RPL
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 2

Brief Summary

The goal of this clinical trial is to learn whether right dorsolateral prefrontal cortex (right DLPFC)-targeted fNIRS-BCI online closed-loop neurofeedback, delivered with slow-wave acoustic cueing, can reduce anxiety symptoms and improve cardiac autonomic regulation in women with recurrent pregnancy loss (RPL) and comorbid anxiety (women aged 18-45 years, right-handed, currently not pregnant or in a missed miscarriage state). The main questions it aims to answer are: Does real neurofeedback increase the proportion of participants who achieve an anxiety treatment response (defined as ≥50% reduction in Hamilton Anxiety Rating Scale \[HAMA\] total score from baseline) compared with sham feedback, at end of treatment and at 3-month follow-up? Is the intervention safe and well tolerated, as reflected by between-group differences in adverse events during the training period? Do brain and autonomic measures show between-group differences during the first formal session, including right DLPFC HbO downregulation, interhemispheric DLPFC synchronisation, heart rate (HR), and heart rate variability (HRV) indices? Researchers will compare real right DLPFC neurofeedback to sham feedback (identical procedures and displays but weakened coupling to real-time neural activity) to see if real neurofeedback improves anxiety outcomes and brain-heart autonomic regulation. Participants will: Complete screening, baseline clinical assessments, and physical examination Be randomly assigned (1:1) to real neurofeedback or sham feedback Complete 3 days of adaptation training followed by 3 weeks of training (15 sessions; one weekday session per day; \~20 minutes each) using a block design with slow-wave acoustic cueing (1 Hz amplitude-modulated tone; 20 s rest + 40 s cueing per block; 20 blocks/session) Undergo fNIRS recording in all sessions, with ECG recorded in session 1 only (for HR/HRV analyses) Receive matched, guideline-informed cognitive-behavioural therapy (CBT) during the intervention period Complete anxiety-related assessments at baseline, \~1 hour after the final session, and 3 months after treatment, with adverse events monitored throughout the intervention period

Conditions

Anxiety; Recurrent Pregnancy Loss

Keywords

Recurrent pregnancy loss; Anxiety disorders; Right dorsolateral prefrontal cortex; Functional near-infrared spectroscopy; Brain-computer interface; Closed-loop neurofeedback; Cardiac autonomic function; Brain-heart coupling

Outcome Measures

Primary Outcomes (1)

• the between-group difference in treatment response

  The investigators will compare the overall proportion of participants achieving response in the real neurofeedback group versus the sham-feedback group across the post-treatment follow-up period, defined by two timepoints: end of treatment and 3-month follow-up. Anxiety symptoms will be assessed using the Hamilton Anxiety Rating Scale (HAMA; ; 14 items, each scored 0-4; total score range 0-56; higher scores indicate greater anxiety severity), and treatment response will be defined a priori as a reduction of at least 50% in total HAMA score from baseline.

  Day 0 (baseline, pre-intervention); Day 24 (end of treatment, within 1 hour after completion of training); 3 months after Day 24.

Secondary Outcomes (7)

• Between-group difference in remission rate.

  Day 0 (baseline, pre-intervention); Day 24 (end of treatment, within 1 hour after completion of training); 3 months after Day 24.

• Between-group difference in continuous HAMA scores.

  Day 0 (baseline, pre-intervention); Day 24 (end of treatment, within 1 hour after completion of training); 3 months after Day 24.

• Between-group difference in downregulation of right DLPFC HbO activation.

  Day 4 after randomisation (first formal training day).

• Between-group difference in interhemispheric synchronisation within the DLPFC.

  Day 4 after randomisation (first formal training day).

• Between-group difference in baseline-corrected heart-rate change.

  Day 4 after randomisation (first formal training day).

Other Outcomes (5)

• The indirect effect of group assignment (real neurofeedback vs sham feedback) on HR change through change in right DLPFC activation.

  Day 4 after randomisation (first formal training day).

• The indirect effect of group assignment on 3-month anxiety improvement through change in right DLPFC activation

  Day 4 after randomisation (first formal training day) and 3 months after Day 24.

• The indirect effect of group assignment on 3-month anxiety improvement through HR change

  Day 4 after randomisation (first formal training day) and 3 months after Day 24.

Study Arms (2)

a real-feedback intervention group

ACTIVE COMPARATOR

Participants will receive right DLPFC targeted fNIRS-BCI online closed-loop neurofeedback delivered with slow-wave acoustic cueing. Training includes a 3-day adaptation phase followed by 3 weeks of formal training (15 weekday visits; about 20 minutes per visit) using a block design (20 blocks per visit; 60 seconds per block: 20 seconds rest + 40 seconds slow-wave acoustic cueing with a 1 Hz sinusoidally amplitude-modulated pure tone at about 60 dB). During each cueing period, real-time right DLPFC activation estimated from fNIRS is displayed as a visual activation bar; participants apply volitional strategies to downregulate activity below a concealed threshold line (T = -3.3; approximating p = 0.001). fNIRS is recorded in all visits; ECG is recorded on the first formal training day only for HR/HRV measures.

Device: Right DLPFC fNIRS-BCI closed-loop neurofeedback (real feedback)

a sham-feedback control group

SHAM COMPARATOR

Participants will receive sham fNIRS-BCI neurofeedback targeting the right DLPFC under procedures identical in appearance and schedule to the real-feedback arm, including the same slow-wave acoustic cueing and block design (20 blocks per visit; 60 seconds per block: 20 seconds rest + 40 seconds cueing with a 1 Hz sinusoidally amplitude-modulated pure tone at about 60 dB). fNIRS is recorded in all visits; ECG is recorded on the first formal training day only for HR/HRV measures. The on-screen interface and concealed threshold line are identical; however, feedback parameters are configured to substantially weaken effective coupling between the displayed activation bar and the participant's instantaneous neural activity (T = -1; approximating p = 0.31), making stable volitional control unlikely while preserving blinding.

Device: Right DLPFC fNIRS-BCI neurofeedback (sham feedback)

Interventions

Right DLPFC fNIRS-BCI closed-loop neurofeedback (real feedback) DEVICE

This device-based intervention delivers fNIRS-BCI online closed-loop neurofeedback targeting the right dorsolateral prefrontal cortex (right DLPFC) with slow-wave acoustic cueing. Participants complete a 3-day adaptation phase followed by 3 weeks of formal training (15 weekday visits; about 20 minutes per visit). Each visit includes 20 blocks (60 seconds per block: 20 seconds rest + 40 seconds slow-wave acoustic cueing with a \~60 dB, 1 Hz sinusoidally amplitude-modulated pure tone). During each cueing period, real-time right DLPFC HbO activity estimated from fNIRS is displayed as a visual activation bar, and participants apply volitional strategies to downregulate activity below a concealed threshold line (T = -3.3; approximating p = 0.001). fNIRS is recorded in all visits; ECG is recorded on the first formal training day only for HR/HRV mechanistic measures.

a real-feedback intervention group

Right DLPFC fNIRS-BCI neurofeedback (sham feedback) DEVICE

This device-based sham intervention uses the same fNIRS-BCI neurofeedback interface, slow-wave acoustic cueing, and training schedule as the real-feedback arm. Participants complete a 3-day adaptation phase followed by 3 weeks of formal training (15 weekday visits; about 20 minutes per visit) using 20 blocks per visit (60 seconds per block: 20 seconds rest + 40 seconds slow-wave acoustic cueing with a \~60 dB, 1 Hz sinusoidally amplitude-modulated pure tone). fNIRS is recorded in all visits; ECG is recorded on the first formal training day only for HR/HRV measures. The displayed activation bar and concealed threshold line are configured to substantially weaken effective coupling to the participant's instantaneous neural activity (threshold setting: T = -1; approximating p = 0.31), making reliable volitional control unlikely while preserving blinding.

a sham-feedback control group

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• (i) Women aged 18-45 years, right-handed;
• (ii) Diagnosis of recurrent pregnancy loss (RPL), defined as ≥2 consecutive spontaneous pregnancy losses occurring before 28 weeks of gestation;
• (iii) Not currently pregnant, or currently in a missed miscarriage state;
• (iv) Meet DSM-5 diagnostic criteria for an anxiety disorder, with at least moderate severity, defined as Clinical Global Impression-Severity (CGI-S) ≥4;
• (v) Hamilton Anxiety Rating Scale (HAMA) ≥16, with 17-item Hamilton Depression Rating Scale (HAMD-17) \<17, to ensure anxiety is the predominant affective disturbance.

You may not qualify if:

• (i) Markedly unstable blood pressure (systolic BP \>180 mmHg or \<90 mmHg);
• (ii) Clinically important comorbid organic diseases, including but not limited to hyperthyroidism, history of atrial fibrillation, sinus bradycardia, major neurological disorders, cerebrovascular disease, or severe pulmonary disease;
• (iii) Significant suicide risk, judged by psychiatric assessment to be unsuitable for study participation;
• (iv) Other severe psychiatric disorders, including substance use disorder, schizophrenia, delusional disorder, unspecified psychotic disorder, bipolar disorder, or delirium;
• (v) Use of any oral antidepressant, anxiolytic, or antipsychotic medication within the past 4 weeks, or fluoxetine within the past 6 weeks, or any long-acting injectable antipsychotic within the past 3 months.

Sponsors & Collaborators

• Shenyang Medical College: lead

Study Sites (2)

The Second Affiliated Hospital of Shenyang Medical College

Shenyang, Liaoning, 110001, China

RECRUITING

Central Hospital Affiliated to Shenyang Medical College

Shenyang, Liaoning, 110024, China

RECRUITING

MeSH Terms

Conditions

Anxiety Disorders

Condition Hierarchy (Ancestors)

Mental Disorders

Study Officials

• Lin Tao, MM

  Shenyang Medical College

  PRINCIPAL INVESTIGATOR

• Yun-En Liu, MD

  Shenyang Medical College

  STUDY CHAIR

• Fei Meng, MD

  Central Hospital Affiliated to Shenyang Medical Collage

  STUDY DIRECTOR

Central Study Contacts

Fei Meng, MD

CONTACT

86-024-85715635; mengfei665@sohu.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Masking (blinding) will be implemented at multiple levels. Participants will be blinded to group assignment, and both groups will receive identical slow-wave acoustic cueing, session structure, instructions, and an indistinguishable on-screen feedback interface with the numerical threshold concealed. Outcome assessors (clinical raters) and data analysts/statisticians will remain blinded throughout data collection and primary analyses. Only the session operator responsible for loading group-specific neurofeedback parameters will be unblinded, and will not participate in outcome assessments or statistical analyses. Emergency unblinding will be permitted only when clinically necessary for participant safety and will be documented according to prespecified procedures.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assoc.Prof.

Model Details: Randomized, sham-controlled, parallel-group, two-arm interventional study model with 1:1 allocation. Eligible women with recurrent pregnancy loss and comorbid anxiety will be assigned to real right DLPFC fNIRS-BCI online closed-loop neurofeedback or sham feedback. Both arms will use an identical training schedule and procedures: a 3-day adaptation phase followed by 3 weeks of formal training (15 sessions; one weekday session/day; \~20 min/session) using a block design (20 blocks/session; 60 s per block: 20 s rest + 40 s slow-wave acoustic cueing with a 1 Hz amplitude-modulated tone). fNIRS will be recorded in all sessions; ECG will be recorded only in session 1 for HR/HRV mechanistic outcomes. Outcomes will be assessed at baseline, end of treatment, and 3-month follow-up.

Study Record Dates

• First Submitted: December 22, 2025
• First Posted: January 8, 2026
• Study Start: December 29, 2025
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): October 30, 2026
• Last Updated: April 24, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

CN (2)