Right Dorsolateral Prefrontal Cortex Closed-loop Neurofeedback for Anxiety in High-ischaemic-risk Chronic Coronary Syndrome (HEART-SET-3)

Right Dorsolateral Prefrontal Cortex Closed-loop Neurofeedback for Anxiety in High-ischaemic-risk Chronic Coronary Syndrome: a Randomized, Sham-controlled Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Anxiety Disorder; Chronic Coronary Syndrome; High Ischemic Risk
• Intervention / Treatment: Device: Active right DLPFC closed-loop fNIRS-BCI neurofeedback; Device: Sham right DLPFC closed-loop fNIRS-BCI neurofeedback

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 214
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yun-En Liu, MD; Phone Number: 86-24-62215130; Email: lye9901@163.com

Study Locations

• China
  • Liaoning
    • Shenyang, Liaoning, China, 110001
      • Second Affiliated Hospital of Shenyang Medical College
      • Contact: Shuai Wang, MD; Phone Number: 86-18002452317; Email: 249404649@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

• Participants will meet high ischemic risk (HIR) criteria by either of the following:

  • 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

  • PCI performed more than 6 months earlier for a non-ACS indication, together with at least 1 of the following risk factors:

    • diabetes mellitus;
    • diffuse multivessel coronary artery disease involving all 3 major coronary vessels;
    • chronic kidney disease with creatinine clearance less than 50 mL/min (recommended to be calculated using the Cockcroft-Gault formula);
    • prior stent thrombosis;
    • peripheral arterial disease;

    • complex PCI, defined by at least 1 of the following:

      • only patent remaining coronary vessel or left main coronary artery stenting;
      • implantation of at least 3 stents or treatment of at least 3 lesions;
      • bifurcation lesion treated with a 2-stent strategy;
      • total stent length greater than 60 mm;
      • PCI for chronic total occlusion.
• Participants will meet DSM-5 diagnostic criteria for an anxiety disorder, confirmed by structured psychiatric interview.
• Participants will have a Hamilton Anxiety Rating Scale (HAMA) score of 16 or higher.
• Participants will have a 17-item Hamilton Depression Rating Scale (HAMD-17) score lower than 17.
• Participants will not have used psychotropic medication, including antidepressants, anxiolytics, or antipsychotics, within 1 month before enrollment; prior psychotropic medication use will not itself exclude participation, provided that a washout period has been completed before enrollment and the medication history is documented.

Exclusion Criteria:

• 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.
• Participants will be excluded if they are pregnant or breastfeeding.

• Participants will be excluded if they have active or recent (within 6 months) severe systemic disease, including any of the following:

  • cerebrovascular disease, including stroke or transient ischemic attack;
  • dementia or severe cognitive impairment;
  • hyperthyroidism;
  • active pulmonary disease;
  • active malignant tumor.
• Participants will be excluded if they have suicidal or homicidal risk based on clinical interview.

• Participants will be excluded if they have other severe psychiatric disorders, including but not limited to:

  • psychotic disorders, such as hallucinations or delusions;
  • bipolar disorder.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active closed-loop neurofeedback; 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; 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.
Sham Comparator: Sham 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 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 months after completion of the 4-week treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	Day 1 of Week 1 of the 4-week treatment period

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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).	From randomization through 4 years after randomization
All-cause mortality		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.	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.	From randomization through 4 years after randomization

Collaborators and Investigators

• Sponsor: Shenyang Medical College
• Investigators: Study Chair: Yun-En Liu, MD, Shenyang Medical College; Principal Investigator: Lin Tao, Assoc.Prof., Shenyang Medical College

Study record dates

Study Major Dates

• Study Start (Estimated): April 19, 2026
• Primary Completion (Estimated): June 20, 2027
• Study Completion (Estimated): February 20, 2031

Study Registration Dates

• First Submitted: April 14, 2026
• First Submitted That Met QC Criteria: April 14, 2026
• First Posted (Actual): April 21, 2026

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: right dorsolateral prefrontal cortex; closed-loop neurofeedback; fNIRS-BCI; psycho-cardiology
• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders
• Other Study ID Numbers: HEART-SET-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No