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

N/ANot Yet RecruitingNCT07561931

Shenyang Medical College60 enrolled

Overview

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.

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.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 45 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: Day 1

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Day 1

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts