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

This proof-of-concept trial investigates whether high-intensity, low-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the right dorsolateral prefrontal cortex (DLPFC) can improve autonomic cardiac regulation in women with recurrent pregnancy loss (RPL) and anxiety. The study explores the lateralised function of the DLPFC in emotional and autonomic control and tests a novel neuromodulation-based strategy to relieve anxiety and sympathetic overactivation.

Recurrent pregnancy loss (RPL) is frequently associated with persistent anxiety and cardiac autonomic dysregulation, forming a vicious cycle that impacts emotional and reproductive outcomes. Neuroimaging studies suggest that lateralised dysfunction of the dorsolateral prefrontal cortex (DLPFC) contributes to both emotional dysregulation and sympathetic overactivation. Building upon the proposed Brain-Heart-Emotion interaction model, we hypothesise that excessive right DLPFC activity amplifies emotional arousal and cardiac sympathetic drive, while insufficient left DLPFC regulation fails to provide cognitive control over anxiety. This imbalance may underlie the comorbidity of anxiety and autonomic dysfunction in women with RPL. This proof-of-concept clinical trial applies high-intensity, low-frequency repetitive transcranial magnetic stimulation (rTMS) to the right DLPFC, aiming to assess its acute neurocardiac effects, specifically rTMS-induced changes in heart rate and heart rate variability (HRV)-two key indicators of autonomic modulation. By using a sequential stimulation paradigm combined with real-time ECG acquisition, this trial will identify the optimal intensity threshold for autonomic modulation and determine whether right DLPFC-targeted rTMS can transiently reduce cardiac sympathetic tone. Findings from this study will inform future trials evaluating rTMS as a precision treatment for anxiety and autonomic dysfunction in RPL, potentially improving psychophysiological health and pregnancy outcomes without relying on pharmacotherapy.

Inclusion Criteria: 1. Female, aged 18-45 years, and right-handed. 2. Diagnosis of recurrent pregnancy loss (RPL), defined as ≥2 consecutive spontaneous miscarriages before 28 weeks of gestation. 3. Currently non-pregnant, or presenting with a missed abortion (no fetal cardiac activity confirmed by ultrasound). 4. Hamilton Anxiety Rating Scale (HAMA) score ≥14 (moderate or greater anxiety) and Hamilton Depression Rating Scale (HAMD-17) score ≤17 (to exclude clinically significant depression). 5. Confirmed diagnosis of at least one DSM-5 anxiety disorder subtype-generalized anxiety disorder (GAD), panic disorder (PD), social anxiety disorder (SAD), or post-traumatic stress disorder (PTSD)-based on a structured or semi-structured psychiatric interview conducted remotely via HIPAA-compliant, encrypted video by a board-certified psychiatrist.--Exclusion Criteria: 1\) Contraindications to transcranial magnetic stimulation (TMS), including metallic implants or a history of epilepsy; 2) Uncontrolled blood pressure (systolic \>180 mmHg or \<90 mmHg); 3) Presence of other major medical conditions, including hyperthyroidism, a history of atrial fibrillation, valvular heart disease, sinus bradycardia, neurological disorders, cerebrovascular disease, or chronic pulmonary disease; 4) Clinically significant suicide risk; 5) A current or past diagnosis of other psychiatric disorders, including substance use disorders, schizophrenia, delusional disorder, unspecified psychotic disorder, bipolar disorder, or delirium.