Altered Interhemispheric DLPFC Coordination and Cardiac Hyperreactivity During Multisensory Aversive Challenge in Recurrent Pregnancy Loss With Comorbid Anxiety

NCT07045818 | Recruiting DMC

• 1 other identifier: NEURO-CARD-fNIRS
• Study Type: observational
• Target: 70
• Locations: 1 country
• Sites: 3

Brief Summary

We propose an exploratory clinical study (NEURO-CARD-2) that employs simultaneous functional near-infrared spectroscopy (fNIRS) and electrocardiography (ECG) to investigate interhemispheric dysfunction in the dorsolateral prefrontal cortex (DLPFC) and its relationship with autonomic sympathetic activation in women with recurrent pregnancy loss (RPL) and comorbid anxiety. Using a standardized multisensory aversive emotional stimulation paradigm, the study will assess cortical and cardiac responses within the framework of the Brain-Heart-Emotion interaction model. The objective is to identify neurobiological signatures underlying emotion-autonomic dysregulation in this population, thereby informing future development of precision-targeted interventions.

Conditions

Recurrent Pregnancy Loss Without Current Pregnancy; Anxiety Disorder

Keywords

recurrent pregnancy loss; anxiety; emotion-autonomic dysregulation; dorsolateral prefrontal cortex; functional near-infrared spectroscopy

Outcome Measures

Primary Outcomes (1)

• Group-dependent hemispheric asymmetry of DLPFC activation during aversive emotional stimulation (group × hemisphere interaction)

  The primary endpoint will be the group-by-hemisphere interaction in task-evoked DLPFC HbO activation during aversive emotional stimulation, comparing women with recurrent pregnancy loss (RPL) with anxiety versus without anxiety. Hemisphere will be defined as right versus left DLPFC, measured within the same participant. The participant-level activation metric will be the DLPFC HbO response estimate (β) derived from the prespecified fNIRS analysis pipeline. The primary hypothesis will be tested using a linear mixed-effects model (LME) fitted by restricted maximum likelihood, with prespecified covariates including age, education, body mass index, miscarriage etiology category, and resting heart rate. The primary confirmatory test will evaluate whether the right-minus-left difference in DLPFC activation differs by group.

  Single-session fNIRS-ECG protocol (Day 1)

Secondary Outcomes (2)

• Group difference in interhemispheric synchronization of DLPFC activity

  Single-session fNIRS-ECG protocol (Day 1)

• Group difference in mean heart-rate increase during aversive emotional stimulation

  Single-session fNIRS-ECG protocol (Day 1)

Other Outcomes (3)

• Support vector machine discrimination of individual joint WTC-HR response profiles in recurrent pregnancy loss with versus without anxiety

  Single-session fNIRS-ECG protocol (Day 1)

• Comparison of adverse events (AEs) and serious adverse events (SAEs) between groups

  Single-session fNIRS-ECG protocol (Day 1)

• Interhemispheric DLPFC coordination as a mediator of the association between anxiety status and task-evoked heart-rate response in recurrent pregnancy loss

  Single-session fNIRS-ECG protocol (Day 1)

Study Arms (2)

Women with recurrent pregnancy loss and comorbid anxiety

Women with recurrent pregnancy loss who will meet DSM-5 criteria for a comorbid anxiety disorder. Participants in this cohort will undergo the same protocol-assigned multisensory aversive stimulation paradigm during simultaneous fNIRS and ECG recording. This cohort will be compared with women with recurrent pregnancy loss without comorbid anxiety to evaluate DLPFC activation, interhemispheric coherence, heart-rate responses, and brain-heart coupling features.

Behavioral: Multisensory aversive emotional challenge task

Women with recurrent pregnancy loss without comorbid anxiety

Women with recurrent pregnancy loss who will not meet DSM-5 criteria for a comorbid anxiety disorder. Participants in this cohort will undergo the same protocol-assigned multisensory aversive stimulation paradigm during simultaneous fNIRS and ECG recording. This cohort will serve as the comparison group for evaluating DLPFC activation, interhemispheric coherence, heart-rate responses, and brain-heart coupling features.

Behavioral: Multisensory aversive emotional challenge task

Interventions

Multisensory aversive emotional challenge task BEHAVIORAL

Participants will undergo a standardized multisensory aversive stimulation paradigm during simultaneous fNIRS and ECG recording. The protocol will use a block design with 12 stimulation blocks, each comprising a 20 s resting phase followed by a 30 s multisensory stimulation phase. During stimulation, participants will view six negative high-arousal images per block selected from the Geneva Affective Picture Database, while concurrently being exposed to time-locked band-limited white noise calibrated to approximately 90 dB(A) and placing both hands on a 0.5 liter bottle filled with ice water maintained at approximately 0 °C. The auditory stimulus will have spectral energy restricted to 2-6 kHz. This standardized multisensory protocol will be used to elicit negative affect and sympathetic arousal.

Women with recurrent pregnancy loss and comorbid anxiety; Women with recurrent pregnancy loss without comorbid anxiety

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Recruitment is expected to occur through obstetrics and gynecology outpatient clinics, as well as community outreach via flyers and media campaigns.

You may qualify if:

• Female, age 18 to 45 years, right-handed;
• Diagnosis of recurrent pregnancy loss, defined as two or more consecutive spontaneous miscarriages before 28 weeks of gestation;
• Not currently pregnant, or diagnosed with missed abortion at the time of assessment;
• Completed a structured psychiatric evaluation conducted by licensed psychiatrists at each center, with diagnostic confirmation according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5);
• For participants assigned to the RPL with anxiety group: meets DSM-5 diagnostic criteria for an anxiety disorder, has a Hamilton Anxiety Rating Scale score of at least 14, and has a 17-item Hamilton Depression Rating Scale score of 17 or lower;
• For participants assigned to the RPL without anxiety group: does not meet DSM-5 diagnostic criteria for an anxiety disorder, has a Hamilton Anxiety Rating Scale score below 14, and has a 17-item Hamilton Depression Rating Scale score of 17 or lower.

You may not qualify if:

• Use of psychotropic medication within the past month, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepines, antipsychotics, or mood stabilizers;
• Unstable or uncontrolled blood pressure, defined as systolic blood pressure greater than 180 mmHg or less than 90 mmHg at screening;
• Major comorbid organic conditions that could affect autonomic or neural measurements, including hyperthyroidism, atrial fibrillation, clinically significant valvular heart disease, prior stroke, epilepsy, traumatic brain injury, or chronic pulmonary disease;
• Significant sensory or communication barriers that could impair task performance or stimulus perception, including hearing impairment, language difficulty, or sensory neuropathy;
• High suicide risk or severe psychiatric comorbidity, including psychotic disorders, bipolar disorder, or substance use disorders;
• Marked intolerance to auditory, visual, or cold stimuli based on medical history or pre-test report;
• Any other condition judged by the study physician to interfere with safe participation in the multisensory aversive stimulation protocol.

Sponsors & Collaborators

• Shenyang Medical College: lead

Study Sites (3)

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

157 Hospital of Liaoning Health Industry Group

Shenyang, Liaoning, 110045, China

RECRUITING

MeSH Terms

Conditions

Anxiety Disorders

Condition Hierarchy (Ancestors)

Mental Disorders

Study Officials

• Yun-En Liu, MD

  Shenyang Medical College

  STUDY CHAIR

• Lin Tao, MM

  Shenyang Medical College

  PRINCIPAL INVESTIGATOR

• Fei Meng, MD

  Central Hospital Affiliated to Shenyang Medical Collage

  STUDY DIRECTOR

• Xiu-Ling Zhang, MD

  The Second Hospital of Shenyang Medical College

  STUDY DIRECTOR

Central Study Contacts

Yun-En Liu, MD

CONTACT

86-24-62215130; lye9901@163.com

Lin Tao, MM

CONTACT

86-18802401698; 1939908868@qq.com

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assoc. Prof.

Study Record Dates

• First Submitted: June 22, 2025
• First Posted: July 1, 2025
• Study Start: June 30, 2025
• Primary Completion: April 30, 2026
• Study Completion: April 30, 2026
• Last Updated: May 6, 2026

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ANALYTIC CODE
• Time Frame: Available at the time of publication of the final article
• Access Criteria: Data will be deposited on the Open Science Framework (https://osf.io) and will be accessible for non-commercial research purposes.

Locations

CN (3)