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高强度低频周期重复经颅磁刺激右侧背外侧前额叶皮层对复发性流产伴焦虑女性心脏自主神经调节的影响

2026年8月26日 更新者：Lin Tao、Shenyang Medical College

高强度低频率周期性右背外侧前额叶皮层rTMS对复发性流产伴焦虑女性心脏自主神经调节影响的随机假对照概念验证试验(NEURO-CARD-rTMS-2)

本临床试验旨在确定对复发性流产（RPL）伴焦虑症女性患者右侧背外侧前额叶皮层（DLPFC）施加高强度、低频率周期性重复经颅磁刺激（rTMS）能否调节心脏自主神经调节功能。 研究主要关注以下问题：

与伪刺激相比，120%静息运动阈值（RMT）节律性低频rTMS是否能在刺激时间窗口内降低心率？

与伪刺激相比，120% RMT rTMS是否会在目标频率（0.0167 Hz）改变心率变异性（HRV）频谱功率？

研究人员将通过对比主动rTMS与伪刺激rTMS，确定主动干预是否能产生可测量的心脏自主神经活动变化。

参与者将：

接受单次rTMS或伪刺激治疗，包含连续20个刺激时间窗口（每个窗口60秒：40秒1Hz刺激加20秒休息），靶向右侧DLPFC；

在整个刺激过程中持续采集心电图（ECG）记录；

在参与前完成临床及精神科评估。

研究概览

地位

招聘中

条件

干预/治疗

详细说明

复发性妊娠丢失（RPL）定义为在胎儿可存活前（即欧洲标准24周或中国标准28周前）发生两次或以上妊娠丢失，影响约2-5%的育龄女性，并带来显著的生理和心理负担。 除了对生殖健康的影响，RPL日益被认为是一种具有全身性后果的疾病，包括焦虑加重、自主神经系统功能改变以及长期心血管风险增加。

新证据表明，在患有RPL和共病焦虑的女性中，慢性心理压力可能导致自主神经系统失调，其特征为交感神经张力增加、迷走神经活动减弱、静息心率升高以及心率变异性（HRV）降低。 这些改变可能形成恶性循环，加剧情绪困扰、自主神经失衡和生殖系统脆弱性。

为解决这一问题，这项随机、假刺激对照的概念验证临床试验将研究针对右侧背外侧前额叶皮层（DLPFC）——这一关键参与情绪调节和自主控制脑区——的低频重复经颅磁刺激（rTMS）能否调节患有RPL和焦虑女性的心脏自主神经功能。

干预方案基于前期剂量探索研究（NEURO-CARD-rTMS-1）的结果，该研究表明以静息运动阈值（RMT）120%的强度进行刺激可显著降低心率且不影响耐受性。 在此基础上，当前试验（NEURO-CARD-rTMS-2）将在右侧DLPFC区施加1Hz节律性rTMS（强度为RMT的120%），通过20个连续刺激窗口（每个窗口60秒：40秒刺激后接20秒休息）实施。 该刺激模式与HRV的极低频（VLF）波段（约0.0167Hz）相匹配，支持频率特异性夹带分析。

主要终点为刺激时间窗口内活性组与假刺激组之间基线校正平均心率的差异。 次要终点包括0.0167Hz处HRV频谱功率变化及脑-心耦合（BHC）——定义为该频率下心率与频谱功率的相关性。 整个过程中将监测安全性结果。

所有心电图（ECG）数据将通过无线蓝牙系统以1000Hz频率持续记录。 参与者将接受基于DSM-5标准的标准化精神评估，并收集关键人口统计学和临床变量（如BMI、血压、用药情况、流产次数及原因）用于协变量分析。

本试验旨在为右侧DLPFC靶向神经调控在改善高风险心理敏感人群自主神经调节方面的可行性和生理效应提供初步机制证据。 若成功，研究结果将支持开发非侵入性、基于脑部的干预措施，以改善患有RPL和焦虑女性的生殖及心血管结局。

研究类型

介入性

注册 (估计的)

48

阶段

  • 不适用

联系人和位置

本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。

学习联系方式

研究联系人备份

学习地点

  • 中国
    • Liaoning
      • Shenyang、Liaoning、中国、110001
        • 招聘中
        • The Second Affiliated Hospital of Shenyang Medical College
        • 接触：
      • Shenyang、Liaoning、中国、110024
        • 招聘中
        • Central Hospital Affiliated to Shenyang Medical College
        • 接触：
      • Shenyang、Liaoning、中国、110086
        • 招聘中
        • 242 Hospital Affiliated to Shenyang Medical College
        • 接触：

参与标准

研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

  • 成人

接受健康志愿者

不

描述

纳入标准：

  • （一）女性，年龄18-45岁，且为右利手；
  • （二）确诊为复发性流产（RPL），定义为妊娠28周前发生两次或两次以上连续自然流产；
  • （三）当前未怀孕或不存在稽留流产状态；
  • （四）符合《精神障碍诊断与统计手册（第五版）》（DSM-5）定义的焦虑障碍诊断标准。

排除标准：

  • （一）存在经颅磁刺激（TMS）禁忌症，如金属植入物或癫痫病史；
  • （二）血压不稳定（收缩压＞180 mmHg或＜90 mmHg）；
  • （三）合并重大器质性疾病，包括甲状腺功能亢进、心房颤动、瓣膜性心脏病、窦性心动过缓、神经系统疾病、脑血管疾病或肺部疾病；
  • （四）存在显著自杀风险；
  • （五）其他精神障碍，包括物质使用障碍、精神分裂症、妄想障碍、未特定精神病性障碍、双相情感障碍或谵妄。

学习计划

本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。

研究是如何设计的？

设计细节

  • 主要用途：治疗
  • 分配：随机化
  • 介入模型：并行分配
  • 屏蔽：双倍的

武器和干预

参与者组/臂
干预/治疗
有源比较器：real rTMS group
Participants in this arm will receive active repetitive transcranial magnetic stimulation (rTMS) delivered to the right dorsolateral prefrontal cortex (DLPFC). In Stage 1, the stimulation protocol consists of 20 consecutive cycles of low-frequency (1 Hz) rTMS at 120% of the resting motor threshold (RMT), with each cycle comprising 40 seconds of stimulation followed by 20 seconds of rest. The total stimulation duration is approximately 20 minutes. Real stimulation is applied with the figure-of-eight coil positioned tangentially to the scalp. After completion of Stage 1 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 continue to receive active stimulation under the same fixed-parameter framework; no re-randomization will be performed.
设备：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-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
假比较器：sham rTMS group
Participants in this arm will receive sham repetitive transcranial magnetic stimulation (rTMS) over the right dorsolateral prefrontal cortex (DLPFC). In Stage 1, the stimulation protocol mimics the active condition in timing and coil placement but involves tilting the coil at a 45-degree angle to the scalp, significantly attenuating magnetic field penetration. This approach preserves the auditory and tactile sensations of stimulation without producing cortical effects. The procedure consists of 20 consecutive cycles of sham stimulation, each comprising 40 seconds of simulated stimulation followed by 20 seconds of rest, lasting approximately 20 minutes in total. After completion of Stage 1 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 continue to receive sham stimu
设备：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 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

研究衡量的是什么？

主要结果指标

结果测量
措施说明
大体时间
主要终点将是通过刺激时间窗口平均得出的基线校正平均心率组间差异。
大体时间：第一场（第一天）
在单次rTMS治疗期间（包含20个刺激周期，每个周期60秒：1Hz频率刺激40秒，随后休息20秒），将通过心电图（1000Hz采样率）持续记录心率。 每个周期将设定50秒分析窗口（-10秒至0秒为刺激前基线期；0秒至+40秒为刺激后期）。 每个周期的基线校正平均心率将计算为刺激后时段（0-40秒）的平均心率减去刺激前10秒基线期（-10至0秒）的平均心率。 随后将每位受试者的数值在20个刺激时间窗口内取平均值，主要终点将对比主动rTMS组与伪刺激组之间这些经过基线校正的平均值。
第一场（第一天）

次要结果测量

结果测量
措施说明
大体时间
经颅磁刺激（rTMS）期间轻度不良事件的发生率，包括刺激部位的头皮不适、面部肌肉抽搐、轻度头痛和头晕。
大体时间：第1阶段（第1天）
该结果将记录在rTMS治疗期间及治疗后1小时即时观察期内，预设轻度不良事件的发生率（发生≥1次事件的参与者比例）。 轻度事件包括刺激部位的头皮不适、面部肌肉抽搐、轻度头痛和头晕。 由经过培训的操作人员使用标准化检查表，结合参与者自述，实时征询并记录事件。 治疗结束时将重新评估生命体征（血压和静息心率）。 若事件具有短暂性、自限性、无需医疗干预且不符合严重不良事件标准（如晕厥或癫痫发作），则归类为轻度事件。 将按组别（真实治疗组与假刺激组）汇总发生率以进行对比。
第1阶段（第1天）
rTMS刺激期间严重不良事件（包括晕厥和癫痫发作）的发生率。
大体时间：第一阶段（第1天）
该结果将量化经颅磁刺激（rTMS）治疗期间及后续1小时观察期内发生的严重不良事件（SAE）发生率（发生≥1次事件的受试者比例）。 SAE将根据ICH-GCP标准定义（指导致死亡、危及生命、需要住院或延长住院时间、导致持续或显著功能障碍/丧失能力、或具有重要医学意义的事件）。 特别关注事件包括晕厥和癫痫发作。 经培训的操作员将使用标准化病例报告表实时监测并记录SAE，包括发生时间、持续时间、采取的措施、结局及与干预措施的相关性。 任何可疑的SAE将启动方案规定的安全程序（立即终止刺激、重新评估生命体征、进行医学评估并根据需要转诊）。 将按组别（主动治疗组 vs 假刺激组）汇总发生率。
第一阶段（第1天）
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.
大体时间：Session 1 (Day 1)
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.
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.
大体时间：Session 1 (Day 1)
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.
Session 1 (Day 1)
The between-group difference in heart rate variability (HRV) spectral power at the target frequency (0.0167 Hz), averaged across stimulation time windows.
大体时间：Session 1 (Day 1)
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.
Session 1 (Day 1)

其他结果措施

结果测量
措施说明
大体时间
Change in Hamilton Anxiety Rating Scale (HAMA) score from baseline
大体时间：Baseline; treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.
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.
Baseline; treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.
Change in Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I), and 17-item Hamilton Depression Rating Scale (HAMD-17) scores
大体时间：Baseline; treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.
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.
Baseline; treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.
Response and remission rates at each assessment time point
大体时间：Treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.
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.
Treatment Week 3; end of treatment at Week 4; 1 month, 3 months, and 6 months after treatment.
Exploratory mediation analyses linking the acute physiological response during the first session to subsequent change in HAMA score
大体时间：First acute session on Day 1; end of treatment at Week 4; 1 month after treatment; 3 months after treatment.
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.
First acute session on Day 1; end of treatment at Week 4; 1 month after treatment; 3 months after treatment.
Participants' subjective judgment of treatment assignment for assessment of blinding performance
大体时间：3 months after treatment.
Blinding assessment will be conducted at the 3-month follow-up visit after treatment in the prespecified exploratory Stage 2 subgroup. Participants will be asked for their subjective judgment of treatment assignment using a 5-point scale: 0, definitely not in the active group; 1, inclined to think not in the active group; 2, unable to judge; 3, inclined to think in the active group; and 4, very certain of being in the active group. These results will be described by group, and group differences in distribution will also be compared.
3 months after treatment.
Safety outcomes in the exploratory Stage 2 subgroup receiving 4 weeks of continuous treatment
大体时间：During the 4-week treatment period; within 30 days after the final treatment session; and at the 3-month and 6-month follow-up visits after treatment.
Safety outcomes will include adverse events and serious adverse events occurring during the 4-week treatment period and within 30 days after the final treatment session, together with unresolved adverse events, hospitalization, unintended pregnancy, significant worsening of psychiatric symptoms, and major changes in concomitant treatment at the 3-month and 6-month follow-up visits after treatment. Safety outcomes will be summarized by group and compared between the active stimulation group and the sham stimulation group. No numerical symptom scale applies to this outcome.
During the 4-week treatment period; within 30 days after the final treatment session; and at the 3-month and 6-month follow-up visits after treatment.

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

Shenyang Medical College

合作者

Central Hospital Affiliated to Shenyang Medical Collage
The Second Hospital of Shenyang Medical College

调查人员

  • 学习椅：Yun-En Liu, MD、Shenyang Medical College
  • 首席研究员：Lin Tao, MM、Shenyang Medical College
  • 研究主任：Fei Meng, MD、Central Hospital Affiliated to Shenyang Medical Collage

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始 (实际的)

2025年11月19日

初级完成 (实际的)

2026年7月22日

研究完成 (估计的)

2026年12月30日

研究注册日期

首次提交

2025年11月14日

首先提交符合 QC 标准的

2025年11月14日

首次发布 (实际的)

2025年11月18日

研究记录更新

最后更新发布 (实际的)

2026年8月28日

上次提交的符合 QC 标准的更新

2026年8月26日

最后验证

2025年12月1日

更多信息

与本研究相关的术语

关键字

其他相关的 MeSH 术语

其他研究编号

  • 2025-038-02_V2

计划个人参与者数据 (IPD)

计划共享个人参与者数据 (IPD)？

是的

IPD 计划说明

经去标识化的个体参与者数据、研究方案及相关支持材料将在正式发表时向公众开放。 数据将存储于国际认可的第三方存储库，供非商业性科研用途使用。

IPD 共享时间框架

在正式出版时提供

IPD 共享支持信息类型

  • 研究方案

药物和器械信息、研究文件

研究美国 FDA 监管的药品

不

研究美国 FDA 监管的设备产品

不

此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.

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