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.
Participants will be aged 18 years or older and will provide written informed consent.
Participants will have chronic coronary syndrome (CCS) with prior coronary stent implantation more than 6 months before enrollment.
Percutaneous coronary intervention (PCI) performed more than 6 months earlier for acute coronary syndrome (ACS), including unstable angina, non-ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction, with implantation of at least 1 coronary stent; or
diabetes mellitus;
Participants will be excluded if they have severe congestive heart failure (New York Heart Association class IV).
Participants will be excluded if they have moderate-to-severe valvular heart disease.
Participants will be excluded if they have a history of atrial fibrillation.
Participants will be excluded if they have unstable blood pressure, defined as systolic blood pressure greater than 180 mmHg or less than 90 mmHg.
Parallel
Active right DLPFC closed-loop fNIRS-BCI neurofeedback
DeviceA closed-loop functional near-infrared spectroscopy brain-computer interface (fNIRS-BCI) neurofeedback intervention targeting the right dorsolateral prefrontal cortex (DLPFC). Participants receive 20 sessions over 4 weeks, delivered once daily on weekdays, with each session lasting approximately 20 minutes. The training uses a 60-second cycle consisting 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 coupled to right DLPFC hemodynamic activity to guide intentional downregulation.
Sham right DLPFC closed-loop fNIRS-BCI neurofeedback
DeviceA sham closed-loop functional near-infrared spectroscopy brain-computer interface (fNIRS-BCI) neurofeedback condition delivered with procedures identical to the active intervention, including the same visit schedule, auditory cues, training duration, interface appearance, and follow-up assessments. Participants receive 20 sessions over 4 weeks, delivered once daily on weekdays, with each session lasting approximately 20 minutes. The feedback signal is not meaningfully coupled to real-time right DLPFC activity.
Hamilton Anxiety Rating Scale (HAMA) total score at 3 months after treatment
Between-group difference in Hamilton Anxiety Rating Scale (HAMA) total score at 3 months after treatment. Lower scores indicate less severe anxiety symptoms.
Hamilton Anxiety Rating Scale (HAMA) total score at end of treatment
Between-group difference in Hamilton Anxiety Rating Scale (HAMA) total score at the end of the 4-week treatment period. Lower scores indicate less severe anxiety symptoms.
HAMA response rate at end of treatment
Proportion of participants with a reduction of 50% or greater from baseline in Hamilton Anxiety Rating Scale (HAMA) total score at the end of treatment.
HAMA response rate at 3 months after treatment
Proportion of participants with a reduction of 50% or greater from baseline in Hamilton Anxiety Rating Scale (HAMA) total score at 3 months after treatment.
Baseline-corrected heart rate change during the first treatment day
Between-group difference in baseline-corrected heart rate change during the task period of the first formal treatment session.
Indirect effect of treatment group on heart rate change mediated by right DLPFC activation
Exploratory mediation effect quantifying whether the association between treatment group and heart rate change is mediated by right dorsolateral prefrontal cortex (DLPFC) activation during the first treatment day.
Indirect effect of treatment group on anxiety improvement mediated by heart rate change
Exploratory mediation effect quantifying whether the association between treatment group and anxiety improvement is mediated by heart rate change, using anxiety outcome assessment at 3 months after treatment.
Time to first major adverse cardiovascular event composite endpoint
Time to first occurrence of any component of the major adverse cardiovascular event (MACE) composite endpoint: cardiovascular death, myocardial infarction, ischemic stroke, systemic embolism, coronary revascularization, or acute limb ischemia.
Time to first atherothrombotic composite endpoint event
Time to first occurrence of any component of the atherothrombotic composite endpoint: myocardial infarction, in-stent thrombosis, ischemic stroke, coronary revascularization, systemic embolism, or acute limb ischemia.
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