Right Dorsolateral Prefrontal Cortex Closed-loop Neurofeedback for Anxiety in High-ischaemic-risk Chronic Coronary Syndrome

Overview

This study is a prospective, randomized, sham-controlled, participant- and assessor-blinded, parallel-group clinical trial designed to evaluate the clinical efficacy, mechanistic effects, and safety of right dorsolateral prefrontal cortex (DLPFC) closed-loop functional near-infrared spectroscopy brain-computer interface (fNIRS-BCI) neurofeedback in patients with high-ischaemic-risk chronic coronary syndrome (CCS) and comorbid anxiety disorder. Participants will be randomly assigned in a 1:1 ratio to active neurofeedback or sham feedback. The intervention consists of 4 weeks of treatment, with 20 sessions in total (1 session per weekday, approximately 20 minutes per session). The primary endpoint is the between-group difference in Hamilton Anxiety Rating Scale (HAMA) score at 3 months after treatment. Secondary endpoints include HAMA score and HAMA response rate at the end of treatment, as well as neurophysiological measures collected during Session 1, including right DLPFC activation, heart rate (HR), and heart rate variability (HRV). Exploratory long-term follow-up will assess cardiovascular and bleeding outcomes through 4 years after randomization.

High-ischaemic-risk chronic coronary syndrome is frequently accompanied by clinically significant anxiety, which may contribute to autonomic imbalance and adverse cardiovascular outcomes. The right dorsolateral prefrontal cortex (DLPFC) is implicated in threat monitoring, negative arousal, and sympathetic activation, and may serve as a cortical target linking emotional symptoms and cardiac autonomic regulation. This study aims to evaluate whether closed-loop fNIRS-BCI neurofeedback targeting the right DLPFC can improve anxiety symptoms, modulate autonomic function, and provide exploratory signals for long-term cardiovascular prognosis in patients with high-ischaemic-risk CCS and comorbid anxiety disorder. This is a prospective, randomized, sham-controlled, participant- and assessor-blinded, parallel-group trial. Eligible participants are adults with chronic coronary syndrome meeting predefined high-ischaemic-risk criteria and a DSM-5 anxiety disorder confirmed by structured psychiatric interview, with HAMA score \>=16 and HAMD-17 score \<17. A total of 214 participants are planned for enrollment and will be randomized 1:1 to active right DLPFC neurofeedback or sham feedback. The intervention consists of 4 weeks of treatment with 20 fNIRS-BCI neurofeedback sessions in total, delivered once daily on weekdays, with each session lasting approximately 20 minutes. The training uses a 60-second rhythmic paradigm composed of 20 seconds of rest and 40 seconds of auditory cueing, with a 1 Hz sinusoidally amplitude-modulated pure tone as the main cue. During training, the system provides real-time feedback derived from right DLPFC hemodynamic activity to guide intentional downregulation. In the sham group, the visual and auditory procedures are identical, but the feedback is not meaningfully coupled to real-time neural activity. ECG is synchronously recorded only during Session 1 for quantification of HR and HRV. The primary endpoint is the between-group difference in HAMA score at 3 months after treatment, analyzed with analysis of covariance (ANCOVA) adjusting for baseline HAMA. Secondary endpoints include the between-group difference in HAMA score at the end of treatment, HAMA response rate at the end of treatment, HAMA response rate at 3 months, and mechanistic neurophysiological endpoints assessed during Session 1, including right DLPFC activation, HR change, and HRV power around 0.0167 Hz. Exploratory endpoints include mediation analyses of the relationships among treatment group, right DLPFC activation, HR change, and anxiety improvement; long-term cardiovascular outcomes including major adverse cardiovascular events, atherothrombotic composite events, cardiovascular composite events, all-cause mortality, bleeding events, and HAMA responder rate at Month 18. Long-term cardiovascular event follow-up will continue from randomization through Year 4, with follow-up at Month 6, Month 12, Month 18, and every 6 months thereafter through Year 4, using outpatient visits, telephone contact, and medical record or registry verification as applicable. Safety assessments include adverse events occurring from randomization through completion of Session 20. All randomized participants with baseline HAMA assessment will be included in the full analysis set according to randomized assignment, and intercurrent events such as initiation of psychotropic medication or psychotherapy during follow-up will be recorded and handled according to the prespecified statistical analysis plan.