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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Clinical Phase

NA

Total Enrollment

46 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-11-20

Study Completion Date

2026-04-20

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Recurrent Pregnancy Loss(RPL) Anxiety

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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. 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.

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Outcome Assessors

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.

Study Groups

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real rTMS group

Participants in this arm will receive active repetitive transcranial magnetic stimulation (rTMS) delivered to the right dorsolateral prefrontal cortex (DLPFC). 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-eight coil positioned tangentially to the scalp.

Group Type ACTIVE_COMPARATOR

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

Intervention Type DEVICE

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.

sham rTMS group

Participants in this arm will receive sham repetitive transcranial magnetic stimulation (rTMS) over the right dorsolateral prefrontal cortex (DLPFC). 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.

Group Type SHAM_COMPARATOR

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

Intervention Type DEVICE

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.

Interventions

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

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.

Intervention Type DEVICE

Eligibility Criteria

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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 diagnostic criteria for an anxiety disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

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 psychiatric disorders, including substance use disorders, schizophrenia, delusional disorder, unspecified psychotic disorder, bipolar disorder, or delirium.

Minimum Eligible Age

18 Years

Maximum Eligible Age

45 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No