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.
(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.
(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;
Parallel
Rhythmic repetitive transcranial magnetic stimulation (rTMS) at 120% RMT, 1 Hz, 60-s cycles
DeviceParticipants 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-eight coil will be positioned tangentially over the scalp at the targeted right DLPFC site. Electrocardiogram (ECG) signals will be recorded continuously throughout the session. After completion of the acute Stage 1 procedure and the post-procedure safety observation period, participants may voluntarily enter a prespecified exploratory Stage 2 subgroup for 4 weeks of continued treatment and follow-up while remaining in their original randomized assignment. Participants who enter Stage 2 will cont
Sham rhythmic repetitive transcranial magnetic stimulation (rTMS) at 120% RMT, 1 Hz, 60-s cycles
DeviceParticipants 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 will be held at a 45-degree angle to the scalp to minimize effective cortical stimulation while preserving the sensory characteristics of the procedure. Electrocardiogram (ECG) signals will be recorded continuously throughout the session. After completion of the acute Stage 1 procedure and the post-procedure safety observation period, participants may voluntarily enter a prespecified exploratory Stage 2 subgroup for 4 weeks of continued treatment and follow-up while remaining in their original ran
The primary endpoint will be the between-group difference in baseline-corrected mean heart rate, averaged across stimulation time windows.
Heart rate (HR) will be continuously recorded via ECG (1,000 Hz) during a single rTMS session comprising 20 stimulation cycles (each 60 s: 40 s stimulation at 1 Hz, then 20 s rest). For each cycle, a 50-s analysis window will be defined (-10 s to 0 s pre-stimulation baseline; 0 s to +40 s post-stimulation). Baseline-corrected mean HR for each cycle will be computed as the mean HR in the post-stimulation segment (0-40 s) minus the mean HR in the 10-s pre-stimulation baseline (-10-0 s). Per-participant values will then be averaged across the 20 stimulation time windows, and the primary endpoint will compare these averaged baseline-corrected means between the active and sham rTMS groups.
The between-group difference in heart rate variability (HRV) spectral power at the target frequency (0.0167 Hz), averaged across stimulation time windows.
HRV spectral power at the target frequency will be derived from R-R interval (RRI) series obtained from continuous ECG recorded at 1,000 Hz. Following resampling, linear detrending, and band-pass filtering, the RRI series will undergo wavelet-based time-frequency analysis. For each stimulation cycle, mean wavelet power within the target frequency band will be quantified over the corresponding analysis window. Window-level estimates will then be averaged across the 20 cycles to obtain a participant-level summary measure, which will be compared between the active and sham groups.
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.
For each participant in the active rTMS group, the linear correlation (Pearson's r) between these two window-wise measures will be calculated across the 20 stimulation time windows.
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.
For each participant in the sham rTMS group, the linear correlation (Pearson's r) between these two window-wise measures will be calculated across the 20 stimulation time windows.
Incidence of mild adverse events during rTMS stimulation, including scalp discomfort at the stimulation site, facial muscle twitching, mild headache, and dizziness.
This outcome will capture the incidence (proportion of participants with ≥1 event) of prespecified mild adverse events during the rTMS session and the immediate 1-hour post-session observation period. Mild events include scalp discomfort at the stimulation site, facial muscle twitching, mild headache, and dizziness. Events will be solicited and recorded in real time by trained operators using a standardized checklist, with participant self-report. Vital signs (blood pressure and resting heart rate) will be reassessed at the end of the session. Events will be classified as mild if transient, self-limited, not requiring medical treatment, and not meeting serious adverse event criteria (e.g., syncope or seizure). Incidence will be summarized by group (active vs sham) for comparison.
Change in Hamilton Anxiety Rating Scale (HAMA) score from baseline
In the prespecified exploratory Stage 2 subgroup, change in HAMA total score from baseline will be assessed at treatment Week 3, at the end of treatment (Week 4), and at 1 month, 3 months, and 6 months after treatment. The HAMA total score ranges from 0 to 56, with higher scores indicating greater anxiety severity.
Change in Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I), and 17-item Hamilton Depression Rating Scale (HAMD-17) scores
In the prespecified exploratory Stage 2 subgroup, CGI-S, CGI-I, and HAMD-17 will be assessed at treatment Week 3, at the end of treatment (Week 4), and at 1 month, 3 months, and 6 months after treatment. The CGI-S score ranges from 1 to 7, with higher scores indicating greater illness severity. The CGI-I score ranges from 1 to 7, with lower scores indicating greater improvement. The HAMD-17 total score ranges from 0 to 52, with higher scores indicating greater depressive symptom severity.
Response and remission rates at each assessment time point
In the prespecified exploratory Stage 2 subgroup, response and remission rates will be calculated separately by group at treatment Week 3, at the end of treatment (Week 4), and at 1 month, 3 months, and 6 months after treatment. Response will be defined as a reduction of at least 50% in HAMA score from baseline. Remission will be defined as HAMA \<8 together with a CGI-I score of 1 or 2. Between-group differences between the active stimulation group and the sham stimulation group will be evaluated at each time point.
Exploratory mediation analyses linking the acute physiological response during the first session to subsequent change in HAMA score
Exploratory mediation analyses will use group as the independent variable, the magnitude of baseline-corrected heart rate deceleration during the first acute session as the mediator, and the change in HAMA score at the end of treatment, 1 month after treatment, and 3 months after treatment as separate dependent variables. The HAMA total score ranges from 0 to 56, with higher scores indicating greater anxiety severity. These analyses are intended to evaluate whether the acute physiological response during the first session may mediate subsequent improvement in anxiety symptoms. Results will be used for mechanistic hypothesis generation and will not be interpreted as confirmatory.
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