Effects of High-frequency Left Dorsolateral Prefrontal rTMS on Heart-brain Coupling in Women With Recurrent Pregnancy Loss and Elevated BMI (NEURO-CARD-BMI)

Effects of High-frequency Left Dorsolateral Prefrontal rTMS on Heart-brain Coupling in Women With Recurrent Pregnancy Loss and Elevated BMI: a Randomized, Sham-controlled Mechanistic Trial (NEURO-CARD-BMI)

This randomized, sham-controlled mechanistic trial will examine whether a single session of high-frequency repetitive transcranial magnetic stimulation, rTMS, applied to the left dorsolateral prefrontal cortex can modify heart-brain coupling in women with recurrent pregnancy loss and elevated body mass index, BMI. Women with recurrent pregnancy loss often experience reproductive, metabolic, and emotional stress at the same time, and this combined vulnerability may be associated with altered autonomic regulation and exaggerated cardiac responses to stress. The left dorsolateral prefrontal cortex is a key brain region involved in cognitive control, emotion regulation, and top-down modulation of autonomic function.

Eligible participants will be randomly assigned in a 1:1 ratio to receive either real or sham rTMS at the same left dorsolateral prefrontal target. The stimulation protocol will use 10 Hz rTMS at 100% motor threshold, delivered in 30 cycles of 5 s stimulation followed by 11 s inter-train interval, with simultaneous 3-lead electrocardiography recording. The primary endpoint will be the between-group difference in mean heart-brain coupling across 30 stimulation cycles. Safety and tolerability will also be monitored. This study is intended to provide mechanistic evidence and methodological support for future multi-session randomized trials in this population.

Study Overview

• Status: Not yet recruiting
• Conditions: Recurrent Pregnancy Loss; Overweight , Obesity; Heart-Brain Coupling
• Intervention / Treatment: Device: Real repetitive transcranial magnetic stimulation; Device: Sham repetitive transcranial magnetic stimulation

Detailed Description

Recurrent pregnancy loss is increasingly recognized not only as a reproductive disorder but also as a condition associated with broader systemic vulnerability. In women with elevated BMI, recurrent pregnancy loss may reflect a composite phenotype characterized by reproductive burden, metabolic stress, emotional distress, and altered autonomic regulation. These converging factors may contribute to exaggerated cardiac responses to stress and early cardiovascular vulnerability. The present study is based on the hypothesis that the left dorsolateral prefrontal cortex, DLPFC, is an important cortical target for top-down modulation of autonomic and heart-brain processes in this population.

This study is designed as a randomized, sham-controlled, single-session mechanistic clinical trial. Sixty women with recurrent pregnancy loss and BMI ≥24 kg/m² will be enrolled and randomly assigned in a 1:1 ratio to real-rTMS or sham-rTMS. Both groups will be stimulated over the same left DLPFC target identified using the adjusted BeamF3 method. In the sham condition, the coil will be positioned over the same target but angled at approximately 45° relative to the scalp to markedly reduce effective cortical stimulation while preserving, as far as possible, the acoustic cue and part of the scalp sensation. Participants and outcome assessors will remain blinded to group assignment; only the operator delivering stimulation will know the assignment on the study day.

The stimulation protocol will use high-frequency rTMS at 10 Hz and 100% motor threshold. Stimulation will be delivered in 30 cycles, each consisting of a 5 s train and an 11 s inter-train interval, for a total of 1,500 pulses over approximately 8 min. During the rTMS-ECG protocol, continuous 3-lead electrocardiography will be recorded at a sampling rate of 1,000 Hz. After preprocessing, heart-brain coupling, HBC, will be quantified from cycle-locked cardiac oscillatory power at the target frequency. HBC is defined in this study as the time-averaged normalized power within the 0.062-0.063 Hz band during each 16 s stimulation cycle. The primary endpoint will be the between-group difference in mean HBC across 30 stimulation cycles, calculated with the Morlet wavelet using the default wavenumber of 6. Secondary endpoints will include mean HBC across 30 cycles under higher-frequency-resolution and higher-temporal-resolution Morlet conditions. Exploratory analyses will include repeated HBC extraction using DoG and Paul wavelets, as well as a group × stimulation progression analysis based on three sequential stages: cycles 1-10, 11-20, and 21-30.

Baseline assessments will include demographic characteristics, reproductive and medical history, comorbidities, medication use, psychiatric ratings, resting heart rate, blood pressure, and 12-lead ECG. Safety monitoring will cover common rTMS-related adverse events, including pain at the stimulation site, facial muscle contraction, mild headache, and dizziness, as well as serious adverse events such as syncope and seizure. After completion of the protocol, participants will remain under observation for 1 h, with reassessment of blood pressure and resting heart rate when clinically indicated. This trial is intended to establish a mechanistic framework for left DLPFC rTMS modulation of heart-brain coupling in women with recurrent pregnancy loss and elevated BMI and to inform the design of future multi-session randomized controlled studies.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lin Tao, MM; Phone Number: 86-18802401698; Email: 1939908868@qq.com

Study Locations

• China
  • Liaoning
    • Shenyang, Liaoning, China, 110024
      • Central Hospital Affiliated to Shenyang Medical College
      • Contact: Fei Meng, MD; Phone Number: 86-024-85715635; Email: mengfei665@sohu.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 1.Female participants aged 18-45 years and right-handed.
• 2.Fulfillment of the prespecified definition of recurrent pregnancy loss in this study, defined as at least two consecutive spontaneous miscarriages occurring before 28 weeks of gestation.
• 3.BMI ≥24 kg/m², classified as overweight or obesity according to the Chinese adult criteria for overweight and obesity.
• 4.Currently not pregnant and in a clinically stable condition. If there is a recent history of missed abortion, appropriate management must have been completed and obstetric assessment must confirm the absence of acute vaginal bleeding, infection, marked abdominal pain, or hemodynamic instability.
• 5.Ability to understand the study procedures, provide written informed consent, and cooperate with scale assessment, transcranial magnetic stimulation safety screening, and the single-session rTMS-ECG protocol.

Exclusion Criteria:

• 1.Presence of contraindications to transcranial magnetic stimulation or elevated seizure risk, including but not limited to epilepsy or a history of unexplained seizures, intracranial ferromagnetic metal implantation, or the presence of electronic or metallic implanted devices within 30 cm of the coil that are judged unsuitable for transcranial magnetic stimulation.
• 2.Current pregnancy.
• 3.Hemodynamic instability or cardiovascular abnormalities that may substantially affect interpretation of the primary endpoint, including systolic blood pressure >180 mmHg or <90 mmHg, atrial fibrillation or other clinically significant arrhythmias, valvular heart disease, marked sinus bradycardia, symptomatic coronary artery disease, or other cardiovascular conditions judged by the research team to make participation unsuitable.
• 4.Uncontrolled major medical or neurologic disorders, particularly those that may substantially affect autonomic state, ECG recording, or interpretation of the primary endpoint, including uncontrolled thyroid dysfunction, uncontrolled diabetes mellitus, significant cerebrovascular disease, neurologic disorders, or active pulmonary disease.
• 5.Presence of significant suicide risk.
• 6.Severe psychiatric disorders that may affect study safety or adherence, including schizophrenia spectrum disorders, bipolar disorder during a manic or hypomanic episode, delirium, and active substance use disorder.
• 7.Severe anxiety or severe depression, defined as a Hamilton Anxiety Rating Scale total score of ≥25 or a 17-item Hamilton Depression Rating Scale total score of ≥24.
• 8.Recent medication-related confounding risk, including current withdrawal from alcohol, sedative-hypnotics, or other relevant substances, or initiation, discontinuation, or dose adjustment within the preceding 2 weeks of medications that may substantially affect seizure threshold, autonomic function, ECG-related indices, or interpretation of the primary endpoint.
• 9.Any other condition judged by the research team to make participation inappropriate.

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
Experimental: Real rTMS; Participants assigned to this arm will receive a single session of real high-frequency rTMS targeting the left dorsolateral prefrontal cortex. Stimulation will be delivered at 10 Hz and 100% motor threshold, with 30 stimulation cycles. Each cycle will include a 5 s train followed by an 11 s inter-train interval. Continuous 3-lead ECG will be recorded during the rTMS-ECG protocol.	Device: Real repetitive transcranial magnetic stimulation; Real rTMS will be delivered to the left dorsolateral prefrontal cortex using the adjusted BeamF3 target. The protocol will consist of 10 Hz stimulation at 100% motor threshold, delivered in 30 cycles, with each cycle including a 5 s train and an 11 s inter-train interval. The total number of pulses will be 1,500. Continuous 3-lead ECG will be recorded during stimulation.; Other Names: real rTMS
Sham Comparator: Sham rTMS; Participants assigned to this arm will receive a single session of sham rTMS at the same left dorsolateral prefrontal cortex target. The coil will be angled approximately 45° relative to the scalp to markedly reduce effective cortical stimulation while preserving, as far as possible, the acoustic cue and part of the scalp sensation. Continuous 3-lead ECG will be recorded during the rTMS-ECG protocol.	Device: Sham repetitive transcranial magnetic stimulation; Sham rTMS will be delivered at the same left dorsolateral prefrontal cortex target as the real-rTMS condition. The coil will be positioned at approximately 45° relative to the scalp to reduce effective cortical stimulation while preserving, as far as possible, the acoustic cue and part of the scalp sensation. Continuous 3-lead ECG will be recorded during the sham protocol.; Other Names: sham rTMS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the between-group difference in mean HBC across 30 stimulation cycles.	Heart-brain coupling, HBC, is defined as the power of RR-interval or heart-rate oscillations induced by repeated TMS and locked to the stimulation-cycle frequency at the target frequency, and is used to quantify rhythmic entrainment effects. In this study, HBC is specifically defined as the time-averaged normalized power within the 0.062-0.063 Hz band during each 16 s stimulation cycle. The primary endpoint will be calculated using the Morlet wavelet, with the wavenumber set to the default value of 6 in order to achieve a relative balance between temporal resolution and frequency resolution. For each participant, 30 cycle-specific HBC values will first be obtained, and these 30 values will then be averaged to derive the participant-level mean HBC; this mean will be entered into the between-group comparison as the primary endpoint.	Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean HBC across 30 stimulation cycles under the higher-frequency-resolution condition.	Under otherwise identical preprocessing and computational procedures, the Morlet wavelet will be used with an increased wavenumber to improve frequency resolution; cycle-specific HBC values will then be recalculated and averaged across 30 cycles to obtain the participant-level mean HBC.	Day 1
Mean HBC across 30 stimulation cycles under the higher-temporal-resolution condition.	2.Under otherwise identical preprocessing and computational procedures, the Morlet wavelet will be used with a decreased wavenumber to improve temporal resolution; cycle-specific HBC values will then be recalculated and averaged across 30 cycles to obtain the participant-level mean HBC.	Day 1
Repeated analysis using the DoG wavelet.	Under the same preprocessing and frequency-band settings as those used for the primary endpoint, the Morlet wavelet will be replaced by the DoG wavelet and the HBC extraction procedure will be repeated to examine the robustness of the findings to the choice of mother wavelet. Because the DoG wavelet is a real-valued wavelet and is more sensitive to local non-oscillatory waveform changes, its results will be used only for exploratory analysis and not as the primary basis for inference.	Day 1
Repeated analysis using the Paul wavelet.	Under the same preprocessing and frequency-band settings as those used for the primary endpoint, the Morlet wavelet will be replaced by the Paul wavelet and the HBC extraction procedure will be repeated to examine the robustness of the findings to the choice of mother wavelet. Because the Paul wavelet has relatively good temporal localization but generally weaker frequency resolution than the Morlet wavelet in the low-frequency range, its results will also be used only for exploratory analysis.	Day 1

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
General adverse events during rTMS	General adverse events will be recorded during the rTMS-ECG protocol and the 1 h post-protocol observation period. Events of interest will include pain at the stimulation site, scalp discomfort, facial muscle contraction, mild headache, and dizziness. Each event will be documented by type, occurrence, timing, and clinical management if applicable.	Day 1
Serious adverse events during rTMS	Serious adverse events will be recorded during the rTMS-ECG protocol and the 1 h post-protocol observation period. Events of interest will include syncope and seizure. Each event will be documented by type, occurrence, timing, severity, clinical management, and outcome if applicable.	Day 1

Collaborators and Investigators

• Sponsor: 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 (Estimated): April 28, 2026
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: April 24, 2026
• First Submitted That Met QC Criteria: April 24, 2026
• First Posted (Actual): May 1, 2026

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: overweight; repetitive transcranial magnetic stimulation; recurrent pregnancy loss; autonomic regulation; elevated BMI; heart-brain coupling; left dorsolateral prefrontal cortex
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Overweight; Obesity
• Other Study ID Numbers: 2026-024-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

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