High-Intensity, Low-Frequency Periodic rTMS Over the Right Dorsolateral Prefrontal Cortex on Cardiac Autonomic Regulation in Women With Recurrent Pregnancy Loss and Anxiety

NCT07233278 | Recruiting DMC

• 1 other identifier: 2025-038-02_V2
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 3

Brief Summary

The goal of this clinical trial is to determine whether high-intensity, low-frequency periodic repetitive transcranial magnetic stimulation (rTMS) applied to the right dorsolateral prefrontal cortex (DLPFC) can modulate cardiac autonomic regulation in women with recurrent pregnancy loss (RPL) and comorbid anxiety. The main questions it aims to answer are: Does 120% resting motor threshold (RMT) rhythmic low-frequency rTMS reduce heart rate during stimulation time windows compared with sham stimulation? Does 120% RMT rTMS alter heart-rate-variability (HRV) spectral power at the target frequency (0.0167 Hz) compared with sham stimulation? Researchers will compare active rTMS with sham rTMS to determine whether the active intervention produces measurable changes in cardiac autonomic activity. Participants will: Undergo a single session of rTMS or sham stimulation consisting of 20 consecutive stimulation time windows (each 60 seconds: 40 seconds of 1-Hz stimulation plus 20 seconds of rest) targeting the right DLPFC; Have continuous electrocardiography (ECG) recordings collected during the entire stimulation session; Complete clinical and psychiatric assessments before participation.

Conditions

Recurrent Pregnancy Loss(RPL); Anxiety

Keywords

Recurrent pregnancy loss; Anxiety; Dorsolateral Prefrontal Cortex; Cardiac Autonomic Regulation; repetitive transcranial magnetic stimulation

Outcome Measures

Primary Outcomes (1)

• The primary endpoint will be the between-group difference in baseline-corrected mean heart rate, averaged across stimulation time windows.

  Heart rate (HR) will be continuously recorded via ECG (1,000 Hz) during a single rTMS session comprising 20 stimulation cycles (each 60 s: 40 s stimulation at 1 Hz, then 20 s rest). For each cycle, a 50-s analysis window will be defined (-10 s to 0 s pre-stimulation baseline; 0 s to +40 s post-stimulation). Baseline-corrected mean HR for each cycle will be computed as the mean HR in the post-stimulation segment (0-40 s) minus the mean HR in the 10-s pre-stimulation baseline (-10-0 s). Per-participant values will then be averaged across the 20 stimulation time windows, and the primary endpoint will compare these averaged baseline-corrected means between the active and sham rTMS groups.

  Session 1 (Day 1)

Secondary Outcomes (5)

• The between-group difference in heart rate variability (HRV) spectral power at the target frequency (0.0167 Hz), averaged across stimulation time windows.

  Session 1 (Day 1)

• The strength of the linear correlation between baseline-corrected mean heart rate and spectral power at 0.0167 Hz, averaged across stimulation time windows, in the active rTMS group.

  Session 1 (Day 1)

• The strength of the linear correlation between baseline-corrected mean heart rate and spectral power at 0.0167 Hz, averaged across stimulation time windows, in the sham rTMS group.

  Session 1 (Day 1)

• Incidence of mild adverse events during rTMS stimulation, including scalp discomfort at the stimulation site, facial muscle twitching, mild headache, and dizziness.

  Session 1 (Day 1)

• Incidence of serious adverse events during rTMS stimulation, including syncope and seizures.

  Session 1 (Day 1)

Other Outcomes (6)

• Change in Hamilton Anxiety Rating Scale (HAMA) score from baseline

  Baseline; treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.

• Change in Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I), and 17-item Hamilton Depression Rating Scale (HAMD-17) scores

  Baseline; treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.

• Response and remission rates at each assessment time point

  Treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.

Study Arms (2)

real rTMS group

ACTIVE COMPARATOR

Participants in this arm will receive active repetitive transcranial magnetic stimulation (rTMS) delivered to the right dorsolateral prefrontal cortex (DLPFC). In Stage 1, the stimulation protocol consists of 20 consecutive cycles of low-frequency (1 Hz) rTMS at 120% of the resting motor threshold (RMT), with each cycle comprising 40 seconds of stimulation followed by 20 seconds of rest. The total stimulation duration is approximately 20 minutes. Real stimulation is applied with the figure-of-eight coil positioned tangentially to the scalp. After completion of Stage 1 and the post-procedure safety observation period, participants may voluntarily enter a prespecified exploratory Stage 2 subgroup for 4 weeks of continued treatment and follow-up while remaining in their original randomized assignment. Participants who enter Stage 2 will continue to receive active stimulation under the same fixed-parameter framework; no re-randomization will be performed.

Device: Rhythmic repetitive transcranial magnetic stimulation (rTMS) at 120% RMT, 1 Hz, 60-s cycles

sham rTMS group

SHAM COMPARATOR

Participants in this arm will receive sham repetitive transcranial magnetic stimulation (rTMS) over the right dorsolateral prefrontal cortex (DLPFC). In Stage 1, the stimulation protocol mimics the active condition in timing and coil placement but involves tilting the coil at a 45-degree angle to the scalp, significantly attenuating magnetic field penetration. This approach preserves the auditory and tactile sensations of stimulation without producing cortical effects. The procedure consists of 20 consecutive cycles of sham stimulation, each comprising 40 seconds of simulated stimulation followed by 20 seconds of rest, lasting approximately 20 minutes in total. After completion of Stage 1 and the post-procedure safety observation period, participants may voluntarily enter a prespecified exploratory Stage 2 subgroup for 4 weeks of continued treatment and follow-up while remaining in their original randomized assignment. Participants who enter Stage 2 will continue to receive sham stimu

Device: Sham rhythmic repetitive transcranial magnetic stimulation (rTMS) at 120% RMT, 1 Hz, 60-s cycles

Interventions

Rhythmic repetitive transcranial magnetic stimulation (rTMS) at 120% RMT, 1 Hz, 60-s cycles DEVICE

Participants assigned to the active rTMS group will receive rhythmic low-frequency repetitive transcranial magnetic stimulation applied over the right dorsolateral prefrontal cortex (DLPFC). In Stage 1, the intervention consists of 20 consecutive stimulation cycles, each comprising 40 seconds of 1 Hz stimulation followed by a 20-second inter-cycle interval, for a total of 60 seconds per cycle. The stimulation intensity is set at 120% of the individual resting motor threshold (RMT). A figure-of-eight coil will be positioned tangentially over the scalp at the targeted right DLPFC site. Electrocardiogram (ECG) signals will be recorded continuously throughout the session. After completion of the acute Stage 1 procedure and the post-procedure safety observation period, participants may voluntarily enter a prespecified exploratory Stage 2 subgroup for 4 weeks of continued treatment and follow-up while remaining in their original randomized assignment. Participants who enter Stage 2 will cont

real rTMS group

Sham rhythmic repetitive transcranial magnetic stimulation (rTMS) at 120% RMT, 1 Hz, 60-s cycles DEVICE

Participants assigned to the sham rTMS group will receive sham rhythmic low-frequency repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex (DLPFC). In Stage 1, the sham procedure matches the active condition in timing, coil position, and auditory and tactile experience, with 20 consecutive sham stimulation cycles, each comprising 40 seconds of simulated stimulation followed by a 20-second inter-cycle interval, for a total of 60 seconds per cycle. The coil will be held at a 45-degree angle to the scalp to minimize effective cortical stimulation while preserving the sensory characteristics of the procedure. Electrocardiogram (ECG) signals will be recorded continuously throughout the session. After completion of the acute Stage 1 procedure and the post-procedure safety observation period, participants may voluntarily enter a prespecified exploratory Stage 2 subgroup for 4 weeks of continued treatment and follow-up while remaining in their original ran

sham rTMS group

Eligibility Criteria

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

You may qualify if:

• (i) Female, aged 18-45 years, and right-handed;
• (ii) Diagnosed with recurrent pregnancy loss (RPL), defined as two or more consecutive spontaneous miscarriages occurring before 28 weeks of gestation;
• (iii) Not currently pregnant or in a state of missed miscarriage;
• (iv) Meeting the DSM-5 diagnostic criteria for GAD, with a HAMA score of at least 16, a CGI-S score of at least 4, and a HAMD-17 score of no more than 17.

You may not qualify if:

• (i) Contraindications to transcranial magnetic stimulation (TMS), such as metallic implants or a history of epilepsy;
• (ii) Unstable blood pressure (systolic \>180 mmHg or \<90 mmHg);
• (iii) Coexisting major organic disorders, including hyperthyroidism, atrial fibrillation, valvular heart disease, sinus bradycardia, neurological diseases, cerebrovascular disease, or pulmonary disorders;
• (iv) Significant suicide risk;
• (v) Other current major psychiatric disorders, including substance use disorder, schizophrenia, delusional disorder, unspecified psychotic disorder, bipolar disorder, or delirium. To preserve diagnostic homogeneity of the study sample, participants whose current primary diagnosis is another anxiety-related disorder will also be excluded, including panic disorder, social anxiety disorder, separation anxiety disorder, specific phobia, obsessive-compulsive and related disorders, and trauma- and stressor-related disorders; Current use of psychotropic medication at screening, or continuous use within the 4 weeks before screening of antidepressants, anxiolytics, antipsychotics, mood stabilizers, or sedative-hypnotics, in order to minimize hemodynamic confounding.

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

242 Hospital Affiliated to Shenyang Medical College

Shenyang, Liaoning, 110086, China

RECRUITING

MeSH Terms

Conditions

Anxiety Disorders

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Mental Disorders

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

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

Central Study Contacts

Fei Meng, MD

CONTACT

86-024-85715635; mengfei665@sohu.com

Lin Tao, MM

CONTACT

86-18802401698; 1939908868@qq.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Participants and outcome assessors will remain blinded to group allocation throughout the study. Only the rTMS operators will be aware of the intervention assignment, as they are responsible for administering either active or sham stimulation. Sham stimulation will be delivered using a 45°-angled coil to replicate the scalp sensations of active rTMS while minimizing cortical effects. All data labeling, processing, and statistical analysis will be conducted under blinded conditions.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assoc.Prof.

Model Details: This study will use a parallel assignment interventional model. Participants will be randomly assigned in a 1:1 ratio to either the active rTMS group or the sham rTMS group.In Stage 1, each participant will receive a single-session intervention under their assigned condition. The intervention will be delivered in a controlled laboratory setting, and both groups will undergo identical procedures except for the presence or absence of effective magnetic stimulation. This design allows for between-group comparison of physiological responses and safety outcomes attributable to the intervention. After completion of the acute Stage 1 procedure and the post-procedure safety observation period, participants may voluntarily enter a prespecified exploratory Stage 2 subgroup for 4 weeks of continued treatment and follow-up while remaining in their original randomized assignment. Participants in Stage 2 will continue to receive active or sham stimulation according to their initial group allocation;

Study Record Dates

• First Submitted: November 14, 2025
• First Posted: November 18, 2025
• Study Start: November 19, 2025
• Primary Completion: June 22, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: July 7, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Available at the time of formal publication

Locations

CN (3)