Overview
We propose an exploratory clinical study (NEURO-CARD-2) that employs simultaneous functional near-infrared spectroscopy (fNIRS) and electrocardiography (ECG) to investigate interhemispheric dysfunction in the dorsolateral prefrontal cortex (DLPFC) and its relationship 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 the framework of the Brain-Heart-Emotion interaction model. The objective is to identify neurobiological signatures underlying emotion-autonomic dysregulation in this population, thereby informing future development of precision-targeted interventions.
Description
Recurrent pregnancy loss (RPL), defined as two or more consecutive pregnancy losses before 24 weeks' gestation, affects an estimated 2-5% of reproductive-aged couples worldwide. Beyond its profound reproductive consequences, RPL carries a heavy psychological burden: approximately 50% of affected women experience chronic anxiety. This emotional distress is more than a mental health concern-it triggers persistent sympathetic activation, evidenced by elevated resting heart rate and diminished heart rate variability (HRV), thus compounding cardiovascular and reproductive risks in a self-reinforcing pathogenic cycle.
Modern psycho-cardiology paradigms, backed by statements from the American Heart Association, underscore the intimate interplay between emotional dysregulation and autonomic dysfunction. Yet the neural mechanisms linking altered central emotion regulation to cardiac autonomic outcomes in women with RPL remain largely elusive-especially in those with comorbid anxiety.
Emerging theories in interoceptive neuroscience suggest that higher-order brain regions could serve as shared neural substrates mediating both anxiety and sympathetic overactivation. In particular, the dorsolateral prefrontal cortex (DLPFC), a critical node within the cognitive control and central autonomic networks, stands out. Evidence from neuroimaging and neuromodulation studies demonstrates hemispheric asymmetry in the DLPFC: the right DLPFC is implicated in threat processing, anxiety generation, and sympathetic arousal, whereas the left DLPFC supports cognitive reappraisal, emotional inhibition, and parasympathetic modulation.
We propose a Brain-Heart-Emotion interaction model in which effective and adaptive autonomic responses depend on synchronized bilateral activation of the DLPFC during negative emotional challenge. Conversely, functional decoupling-manifested as right-lateralized DLPFC dominance-may undermine emotion regulation capacity and precipitate sympathetic overdrive. In women with RPL and comorbid anxiety, this decoupling is posited to drive the convergence of emotional dysregulation and cardiac dysfunction, thereby elevating the risk of adverse reproductive and cardiovascular outcomes.
To test this hypothesis, we have designed a prospective, exploratory clinical study employing simultaneous functional near-infrared spectroscopy (fNIRS) and electrocardiography (ECG) during a standardized multisensory emotional provocation paradigm. We will investigate patterns of interhemispheric DLPFC activation and their relationship to heart rate dynamics in women with recurrent pregnancy loss (RPL), in the presence versus absence of comorbid anxiety, within the proposed Brain-Heart-Emotion framework.
If confirmed, these findings will provide both mechanistic insight and empirical justification for neurobiologically informed, precision-targeted interventions. In particular, they may support the application of inhibitory neuromodulation targeting the right DLPFC, with the potential to deliver multidimensional therapeutic benefits-including enhanced emotional regulation, restoration of autonomic balance, reduced long-term cardiovascular risk, and improved reproductive outcomes in this high-risk population.
Eligibility
Inclusion Criteria:
- Female, aged 18-45 years, right-handed;
- Diagnosis of recurrent pregnancy loss-defined as ≥2 consecutive spontaneous miscarriages before 28 weeks' gestation;
- Not currently pregnant, or diagnosed with missed abortion at the time of assessment;
- Completed structured psychiatric evaluation by licensed psychiatrists at each center, with diagnostic confirmation per DSM-5.
Exclusion Criteria:
- Use of psychotropic medications in the past month (e.g., SSRIs, SNRIs, TCAs, benzodiazepines, antipsychotics, mood stabilizers);
- Unstable or uncontrolled hypertension (SBP > 180 mmHg or < 90 mmHg);
- Major comorbid organic conditions (e.g., hyperthyroidism, atrial fibrillation, valvular heart disease, stroke, epilepsy, traumatic brain injury, chronic pulmonary disease);
- Significant sensory or communication barriers (e.g., hearing impairment, language difficulty, sensory neuropathy) that could impair task performance or stimulus perception;
- High suicide risk or severe psychiatric comorbidity (e.g., schizophrenia, bipolar disorder, psychotic disorders, substance use disorders);
- Extreme intolerance to auditory, visual, or cold stimuli, based on medical history or pre-test report;
- Any other condition judged by the research physician to interfere with participation in the multisensory emotional stimulation protocol.