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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
46
Participants in the real rTMS group will receive rhythmic low-frequency repetitive transcranial magnetic stimulation (rTMS) applied over the right dorsolateral prefrontal cortex (DLPFC). The intervention consists of 20 consecutive stimulation cycles, each comprising 40 seconds of 1 Hz stimulation followed by a 20-second inter-cycle interval, totaling 60 seconds per cycle. The stimulation intensity is set at 120% of the individual's 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 synchronously throughout the session for heart rate variability analysis.
Central Hospital Affiliated to Shenyang Medical Collage
Shenyang, Liaoning, China
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.
Time frame: Session 1 (Day 1)
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.
Time frame: Session 1 (Day 1)
The strength of the linear correlation (i.e., brain-heart coupling, BHC) 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.
Time frame: Session 1 (Day 1)
The strength of the linear correlation (i.e., BHC) 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.
Time frame: 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.
Time frame: 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).
Time frame: Session 1 (Day 1)
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