Altered Interhemispheric DLPFC Coordination and Cardiac Hyperreactivity During Multisensory Aversive Challenge in Recurrent Pregnancy Loss With Comorbid Anxiety

Altered Interhemispheric DLPFC Coordination and Cardiac Hyperreactivity During Multisensory Aversive Challenge in Recurrent Pregnancy Loss With Comorbid Anxiety: a Multicenter Simultaneous fNIRS-ECG Study (NEURO-CARD-fNIRS)

This exploratory clinical study, NEURO-CARD-2, will use simultaneous functional near-infrared spectroscopy (fNIRS) and electrocardiography (ECG) to investigate interhemispheric dysfunction in the dorsolateral prefrontal cortex (DLPFC) and its association with autonomic sympathetic activation in women with recurrent pregnancy loss (RPL) and comorbid anxiety. Using a standardized multisensory aversive emotional stimulation paradigm, the study will assess cortical and cardiac responses within a Brain-Heart-Emotion interaction framework. The objective will be to identify neurobiological signatures of emotion-autonomic dysregulation in this population and to inform the future development of precision-targeted interventions.

For this protocol, recurrent pregnancy loss (RPL) was defined as two or more consecutive spontaneous miscarriages before 28 weeks of gestation. RPL affects approximately 2-5% of reproductive-age couples worldwide and imposes a substantial clinical and emotional burden. In addition to its reproductive consequences, RPL is associated with a substantial psychological burden, and approximately 50% of affected women experience chronic anxiety. This emotional burden has been linked to persistent sympathetic activation, including elevated resting heart rate and reduced heart rate variability, which may contribute to cardiovascular and reproductive risk.

Contemporary psycho-cardiology models, including statements from the American Heart Association, emphasize the close relationship between emotional dysregulation and autonomic dysfunction. The neural mechanisms linking altered central emotion regulation to cardiac autonomic outcomes in women with RPL remain insufficiently characterized, particularly in those with comorbid anxiety.

Emerging work in interoceptive neuroscience suggests that higher-order brain regions may provide shared neural substrates for anxiety and sympathetic overactivation. The dorsolateral prefrontal cortex (DLPFC), a key node in the cognitive control network and central autonomic network, is of particular interest. Neuroimaging and neuromodulation studies have shown hemispheric asymmetry within the DLPFC. The right DLPFC has been associated with threat processing, anxiety, and sympathetic arousal, whereas the left DLPFC has been associated with cognitive reappraisal, emotional inhibition, and parasympathetic modulation.

A Brain-Heart-Emotion interaction model underlies this study. Within this framework, effective autonomic adaptation during negative emotional challenge is hypothesized to depend on coordinated bilateral DLPFC recruitment. Functional decoupling, expressed as right-lateralized DLPFC dominance, may weaken emotion regulation capacity and promote sympathetic overactivation. In women with RPL and comorbid anxiety, this pattern is hypothesized to contribute to the convergence of emotional dysregulation and cardiac dysfunction, with potential implications for reproductive and cardiovascular risk.

To evaluate this hypothesis, this prospective exploratory clinical study will use simultaneous fNIRS and ECG during a standardized multisensory emotional provocation paradigm. Patterns of interhemispheric DLPFC activation and their associations with heart rate dynamics will be examined in women with RPL with and without comorbid anxiety within the proposed Brain-Heart-Emotion framework.

If confirmed, the findings may provide mechanistic insight and empirical support for neurobiologically informed precision-targeted interventions. Potential implications may include support for inhibitory neuromodulation targeting the right DLPFC, with possible benefits for emotional regulation, autonomic balance, long-term cardiovascular risk reduction, and reproductive outcomes in this high-risk population.

Inclusion Criteria:

• Female, age 18 to 45 years, right-handed;
• Diagnosis of recurrent pregnancy loss, defined as two or more consecutive spontaneous miscarriages before 28 weeks of gestation;
• Not currently pregnant, or diagnosed with missed abortion at the time of assessment;
• Completed a structured psychiatric evaluation conducted by licensed psychiatrists at each center, with diagnostic confirmation according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5);
• For participants assigned to the RPL with anxiety group: meets DSM-5 diagnostic criteria for generalized anxiety disorder, has a Hamilton Anxiety Rating Scale score of at least 14, and has a 17-item Hamilton Depression Rating Scale score of 17 or lower;
• For participants assigned to the RPL without anxiety group: does not meet DSM-5 diagnostic criteria for generalized anxiety disorder, has a Hamilton Anxiety Rating Scale score below 14, and has a 17-item Hamilton Depression Rating Scale score of 17 or lower.

Exclusion Criteria:

• Use of psychotropic medication within the past month, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepines, antipsychotics, or mood stabilizers;
• Unstable or uncontrolled blood pressure, defined as systolic blood pressure greater than 180 mmHg or less than 90 mmHg at screening;
• Major comorbid organic conditions that could affect autonomic or neural measurements, including hyperthyroidism, atrial fibrillation, clinically significant valvular heart disease, prior stroke, epilepsy, traumatic brain injury, or chronic pulmonary disease;
• Significant sensory or communication barriers that could impair task performance or stimulus perception, including hearing impairment, language difficulty, or sensory neuropathy;
• High suicide risk or severe psychiatric comorbidity, including psychotic disorders, bipolar disorder, or substance use disorders;
• Marked intolerance to auditory, visual, or cold stimuli based on medical history or pre-test report;
• Any other condition judged by the study physician to interfere with safe participation in the multisensory aversive stimulation protocol.