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

Official title

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)

Overview

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.

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.

Interventions

• 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-e
• 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 wi

Primary outcome measures

• The primary endpoint will be the between-group difference in baseline-corrected mean heart rate, averaged across stimulation time windows. [Time frame: Session 1 (Day 1)]

Secondary outcome measures (5)

• The between-group difference in heart rate variability (HRV) spectral power at the target frequency (0.0167 Hz), averaged across stimulation time windows. [Time frame: 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. [Time frame: 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. [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. [Time frame: Session 1 (Day 1)]
• Incidence of serious adverse events during rTMS stimulation, including syncope and seizures. [Time frame: Session 1 (Day 1)]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

China · 3 centers

• The Second Affiliated Hospital of Shenyang Medical College — Shenyang
• Central Hospital Affiliated to Shenyang Medical College — Shenyang
• 242 Hospital Affiliated to Shenyang Medical College — Shenyang

Identifiers

NCT: NCT07233278 · 2025-038-02_V2

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗