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

High-intensity, Low-frequency Periodic rTMS Over the Right Dorsolateral Prefrontal Cortex for Acute Cardiac Autonomic Regulation in Women With Recurrent Pregnancy Loss and Generalized Anxiety Disorder: a Randomized, Sham-controlled Mechanistic Trial (NEURO-CARD-rTMS-2)

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.

Study Overview

• Status: Recruiting
• Conditions: Anxiety; Recurrent Pregnancy Loss(RPL)
• Intervention / Treatment: Device: Rhythmic repetitive transcranial magnetic stimulation (rTMS) at 120% RMT, 1 Hz, 60-s cycles; Device: Sham rhythmic repetitive transcranial magnetic stimulation (rTMS) at 120% RMT, 1 Hz, 60-s cycles

Detailed Description

Recurrent pregnancy loss (RPL), defined as the loss of two or more pregnancies before viability (i.e., 24 weeks by European standards or 28 weeks by Chinese criteria), affects approximately 2-5% of women of reproductive age and represents a significant physical and psychological burden. Beyond its implications for reproductive health, RPL is increasingly recognized as a condition associated with systemic consequences, including heightened anxiety, altered autonomic nervous system function, and increased long-term cardiovascular risk.

Emerging evidence suggests that in women with RPL and comorbid anxiety, chronic psychological stress may lead to dysregulation of the autonomic nervous system, characterized by increased sympathetic tone, reduced vagal activity, elevated resting heart rate, and decreased heart rate variability (HRV). These alterations may create a maladaptive feedback loop that reinforces emotional distress, autonomic imbalance, and reproductive vulnerability.

To address this issue, this randomized, sham-controlled, proof-of-concept clinical trial will investigate whether low-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the right dorsolateral prefrontal cortex (DLPFC)-a region critically involved in emotion regulation and autonomic control-can modulate cardiac autonomic function in women with RPL and anxiety.

The intervention protocol is based on findings from a prior dose-finding study (NEURO-CARD-rTMS-1), which indicated that stimulation at 120% of resting motor threshold (RMT) produced significant reductions in heart rate without compromising tolerability. Building on this, the current trial (NEURO-CARD-rTMS-2) will apply 1-Hz rhythmic rTMS at 120% RMT over the right DLPFC, delivered in 20 consecutive stimulation windows (each 60 seconds long: 40 seconds of stimulation followed by 20 seconds of rest). This stimulation paradigm aligns with the very-low-frequency (VLF) band of HRV (~0.0167 Hz), enabling frequency-specific entrainment analysis.

The primary endpoint will be the difference in baseline-corrected mean heart rate during the stimulation time windows between the active and sham groups. Secondary endpoints include changes in HRV spectral power at 0.0167 Hz and brain-heart coupling (BHC), defined as the correlation between heart rate and spectral power at this frequency. Safety outcomes will be monitored throughout the procedure.

All electrocardiographic (ECG) data will be recorded continuously at 1000 Hz using a wireless Bluetooth system. Participants will undergo standardized psychiatric assessments based on DSM-5 criteria, and key demographic and clinical variables (e.g., BMI, blood pressure, medication use, number and cause of miscarriages) will be collected for covariate analysis.

This trial aims to provide initial mechanistic evidence for the feasibility and physiological efficacy of right DLPFC-targeted neuromodulation in improving autonomic regulation in a high-risk, psychologically sensitive population. If successful, the findings will support the development of non-invasive, brain-based interventions to improve both reproductive and cardiovascular outcomes in women with RPL and anxiety.

• Study Type: Interventional
• Enrollment (Estimated): 46
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lin Tao, MM; Phone Number: 86-18802401698; Email: 1939908868@qq.com
• Study Contact Backup: Name: Fei Meng, MD; Phone Number: 86-024-85715635; Email: mengfei665@sohu.com

Study Locations

• China
  • Liaoning
    • Shenyang, Liaoning, China, 110001
      • Recruiting
      • The Second Affiliated Hospital of Shenyang Medical College
      • Contact: Xiu-Ling Zhang, MD; Phone Number: 86-024-31236568; Email: 2238501927@qq.com
    • Shenyang, Liaoning, China, 110024
      • Recruiting
      • Central Hospital Affiliated to Shenyang Medical College
      • Contact: Fei Meng, MD; Phone Number: 86-024-85715635; Email: mengfei665@sohu.com
    • Shenyang, Liaoning, China, 110086
      • Recruiting
      • 242 Hospital Affiliated to Shenyang Medical College
      • Contact: Lu-Wei Zhang, MD; Phone Number: 86-13904005901; Email: 2907311795@qq.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• (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.

Exclusion Criteria:

• (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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: real rTMS group; 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; 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
Sham Comparator: sham rTMS group; 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; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
The between-group difference in heart rate variability (HRV) spectral power at the target frequency (0.0167 Hz), averaged across stimulation time windows.	HRV spectral power at the target frequency will be derived from R-R interval (RRI) series obtained from continuous ECG (1,000 Hz). RRI will be resampled at 1 Hz via cubic-spline interpolation, linearly detrended, and band-pass filtered. Time-frequency analysis will use a derivative-of-Gaussian (DoG) wavelet. For each stimulation cycle (60 s; 40 s stimulation + 20 s rest), a 50-s stimulation time window will be defined (-10 s to +40 s relative to stimulation onset). Frequency-specific entrainment power will be computed as the mean wavelet power within 0.015-0.018 Hz inside this window. Per-participant estimates will then be averaged across the 20 stimulation time windows, and active versus sham groups will be compared.	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.	This outcome will capture the incidence (proportion of participants with ≥1 event) of prespecified mild adverse events during the rTMS session and the immediate 1-hour post-session observation period. Mild events include scalp discomfort at the stimulation site, facial muscle twitching, mild headache, and dizziness. Events will be solicited and recorded in real time by trained operators using a standardized checklist, with participant self-report. Vital signs (blood pressure and resting heart rate) will be reassessed at the end of the session. Events will be classified as mild if transient, self-limited, not requiring medical treatment, and not meeting serious adverse event criteria (e.g., syncope or seizure). Incidence will be summarized by group (active vs sham) for comparison.	Session 1 (Day 1)
Incidence of serious adverse events during rTMS stimulation, including syncope and seizures.	This outcome will quantify the incidence (proportion of participants with ≥1 event) of serious adverse events (SAEs) occurring during the rTMS session and the subsequent 1-hour observation period. SAEs will be defined per ICH-GCP criteria (events that are fatal, life-threatening, require inpatient hospitalization or prolong an existing hospitalization, result in persistent or significant disability/incapacity, or are otherwise medically important). Events of special interest include syncope and seizures. Trained operators will actively monitor and document SAEs in real time using standardized case-report forms, including onset time, duration, actions taken, outcome, and relatedness to the intervention. Any suspected SAE will trigger protocol-specified safety procedures (immediate termination of stimulation, vital-sign reassessment, medical evaluation, and referral as needed). Incidence will be summarized by group (active vs sham).	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.	For each participant in the active rTMS group, the linear correlation (Pearson's r) between these two window-wise measures will be calculated across the 20 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 sham rTMS group.	For each participant in the sham rTMS group, the linear correlation (Pearson's r) between these two window-wise measures will be calculated across the 20 stimulation time windows.	Session 1 (Day 1)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hamilton Anxiety Rating Scale (HAMA) score from baseline	In the prespecified exploratory Stage 2 subgroup, change in HAMA total score from baseline will be assessed at treatment Week 3, at the end of treatment (Week 4), and at 1 month, 3 months, and 6 months after treatment. The HAMA total score ranges from 0 to 56, with higher scores indicating greater anxiety severity.	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	In the prespecified exploratory Stage 2 subgroup, CGI-S, CGI-I, and HAMD-17 will be assessed at treatment Week 3, at the end of treatment (Week 4), and at 1 month, 3 months, and 6 months after treatment. The CGI-S score ranges from 1 to 7, with higher scores indicating greater illness severity. The CGI-I score ranges from 1 to 7, with lower scores indicating greater improvement. The HAMD-17 total score ranges from 0 to 52, with higher scores indicating greater depressive symptom severity.	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	In the prespecified exploratory Stage 2 subgroup, response and remission rates will be calculated separately by group at treatment Week 3, at the end of treatment (Week 4), and at 1 month, 3 months, and 6 months after treatment. Response will be defined as a reduction of at least 50% in HAMA score from baseline. Remission will be defined as HAMA <8 together with a CGI-I score of 1 or 2. Between-group differences between the active stimulation group and the sham stimulation group will be evaluated at each time point.	Treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.
Exploratory mediation analyses linking the acute physiological response during the first session to subsequent change in HAMA score	Exploratory mediation analyses will use group as the independent variable, the magnitude of baseline-corrected heart rate deceleration during the first acute session as the mediator, and the change in HAMA score at the end of treatment, 1 month after treatment, and 3 months after treatment as separate dependent variables. The HAMA total score ranges from 0 to 56, with higher scores indicating greater anxiety severity. These analyses are intended to evaluate whether the acute physiological response during the first session may mediate subsequent improvement in anxiety symptoms. Results will be used for mechanistic hypothesis generation and will not be interpreted as confirmatory.	First acute session on Day 1; end of treatment at Week 4; 1 month after treatment; 3 months after treatment.
Participants' subjective judgment of treatment assignment for assessment of blinding performance	Blinding assessment will be conducted at the 3-month follow-up visit after treatment in the prespecified exploratory Stage 2 subgroup. Participants will be asked for their subjective judgment of treatment assignment using a 5-point scale: 0, definitely not in the active group; 1, inclined to think not in the active group; 2, unable to judge; 3, inclined to think in the active group; and 4, very certain of being in the active group. These results will be described by group, and group differences in distribution will also be compared.	3 months after treatment.
Safety outcomes in the exploratory Stage 2 subgroup receiving 4 weeks of continuous treatment	Safety outcomes will include adverse events and serious adverse events occurring during the 4-week treatment period and within 30 days after the final treatment session, together with unresolved adverse events, hospitalization, unintended pregnancy, significant worsening of psychiatric symptoms, and major changes in concomitant treatment at the 3-month and 6-month follow-up visits after treatment. Safety outcomes will be summarized by group and compared between the active stimulation group and the sham stimulation group. No numerical symptom scale applies to this outcome.	During the 4-week treatment period; within 30 days after the final treatment session; and at the 3-month and 6-month follow-up visits after treatment.

Collaborators and Investigators

• Sponsor: Shenyang Medical College
• Collaborators: Central Hospital Affiliated to Shenyang Medical Collage; The Second Hospital of Shenyang Medical College
• Investigators: Study Chair: Yun-En Liu, MD, Shenyang Medical College; Principal Investigator: Lin Tao, MM, Shenyang Medical College; Study Director: Fei Meng, MD, Central Hospital Affiliated to Shenyang Medical Collage

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2025
• Primary Completion (Estimated): May 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: November 14, 2025
• First Submitted That Met QC Criteria: November 14, 2025
• First Posted (Actual): November 18, 2025

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Anxiety; repetitive transcranial magnetic stimulation; Dorsolateral Prefrontal Cortex; Recurrent pregnancy loss; Cardiac Autonomic Regulation
• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders; Therapeutics; Magnetic Field Therapy; Transcranial Magnetic Stimulation
• Other Study ID Numbers: 2025-038-02_V2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data, study protocol and supporting materials will be made publicly available at the time of formal publication. Data will be hosted on an internationally recognised third-party repository and accessible for non-commercial scientific use.
• IPD Sharing Time Frame: Available at the time of formal publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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