An interventional study of Active right DLPFC closed-loop fNIRS-BCI neurofeedback and Sham right DLPFC closed-loop fNIRS-BCI neurofeedback in Chronic Coronary Syndrome, Anxiety Disorder and High Ischemic Risk, sponsored by Shenyang Medical College. Not yet recruiting at 1 site in China. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-04-21.
Sponsored by Shenyang Medical College · Not applicable, Interventional, and Treatment
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.
Participants will meet high ischemic risk (HIR) criteria by either of the following:
PCI performed more than 6 months earlier for a non-ACS indication, together with at least 1 of the following risk factors:
complex PCI, defined by at least 1 of the following:
Exclusion Criteria:
Participants will be excluded if they have active or recent (within 6 months) severe systemic disease, including any of the following:
Participants will be excluded if they have other severe psychiatric disorders, including but not limited to:
Participants assigned to this arm receive active right dorsolateral prefrontal cortex (DLPFC) closed-loop fNIRS-BCI neurofeedback. Treatment consists of 20 sessions over 4 weeks (1 session per weekday, approximately 20 minutes per session). The feedback signal is meaningfully coupled to real-time right DLPFC activity. Session 1 includes synchronized ECG recording for HR and HRV assessment.
Device: Active right DLPFC closed-loop fNIRS-BCI neurofeedback
Participants assigned to this arm undergo procedures identical to the active arm, including the same visit schedule, auditory cues, training duration, interface appearance, and follow-up assessments. Treatment consists of 20 sessions over 4 weeks (1 session per weekday, approximately 20 minutes per session). The feedback signal is not meaningfully coupled to real-time right DLPFC activity. Session 1 includes synchronized ECG recording for HR and HRV assessment.
Device: Sham right DLPFC closed-loop fNIRS-BCI neurofeedback
A 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.
A 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.
Time frame: 3 months after completion of the 4-week treatment period
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.
Time frame: At the end of Week 4 of treatment
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.
Time frame: At the end of Week 4 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.
Time frame: 3 months after completion of the 4-week treatment period
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.
Time frame: Day 1 of Week 1 of the 4-week treatment period
Right dorsolateral prefrontal cortex HbO activation during the first treatment day
Between-group difference in right dorsolateral prefrontal cortex (DLPFC) oxyhemoglobin (HbO) activation measured by functional near-infrared spectroscopy during the task period of the first formal treatment session.
Time frame: Day 1 of Week 1 of the 4-week treatment period
Heart rate variability spectral power around 0.0167 Hz during the first treatment day
Between-group difference in heart rate variability spectral power around 0.0167 Hz, derived from wavelet time-frequency analysis during the task period of the first formal treatment session.
Time frame: Day 1 of Week 1 of the 4-week treatment period
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.
Time frame: Day 1 of Week 1 of the 4-week treatment period
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 frame: 3 months after completion of the 4-week treatment period
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 frame: From randomization through 4 years after randomization
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.
Time frame: From randomization through 4 years after randomization
Time to first cardiovascular composite endpoint event
Time to first occurrence of any component of the cardiovascular composite endpoint: cardiovascular death, myocardial infarction, or stroke (ischemic or hemorrhagic).
Time frame: From randomization through 4 years after randomization
All-cause mortality
Time frame: From randomization through 4 years after randomization
HAMA responder rate at Month 18
Proportion of participants with a reduction of 50% or greater from baseline in Hamilton Anxiety Rating Scale (HAMA) total score at the Month 18 follow-up assessment.
Time frame: 18 months after completion of the 4-week treatment period
Time to first bleeding event meeting ISTH criteria
Time to first bleeding event meeting International Society on Thrombosis and Haemostasis (ISTH) criteria, including minor bleeding, clinically relevant non-major bleeding, or major bleeding.
Time frame: From randomization through 4 years after randomization
Plan to share: Yes
Supporting information: Study protocol
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Shenyang Medical College