Closed-Loop Neurofeedback Targeting the Left Dorsolateral Prefrontal Cortex for Cardiac Autonomic Modulation in Coronary Artery Disease With Anxiety - A Randomized, Sham-Controlled Trial (HEART-SET-2)

This exploratory clinical trial is grounded in the emerging field of psycho-cardiology, which highlights the close interaction between mental health and cardiovascular outcomes in patients with coronary heart disease(CHD). Converging epidemiological data indicate that anxiety is common in CHD and is associated with higher rates of in-hospital complications, rehospitalisation, major adverse cardiovascular events, and mortality. Experimental and clinical studies further suggest that heightened sympathetic arousal and disturbed cardiac autonomic regulation may form a physiological link between anxiety and adverse cardiac prognosis in this population.

At the neural level, the central autonomic network(CAN)-including the insula, cingulate cortex, prefrontal cortex, amygdala, hypothalamus, and brainstem nuclei-provides a structural and functional substrate for brain-heart coupling. Within this network, the dorsolateral prefrontal cortex(DLPFC) plays a key role in executive control, conflict monitoring, and cognitive reappraisal, and interacts with interoceptive and autonomic control circuits. Prior work supports functional lateralisation: the right DLPFC is more strongly associated with threat monitoring and sympathetic mobilisation, whereas the left DLPFC is more involved in top-down cognitive control and reappraisal. Under stress, robust recruitment of left DLPFC activity is thought to dampen excessive interoceptive drive and hyperarousal, potentially facilitating engagement of parasympathetic pathways and supporting emotional regulation.

On this mechanistic background, the present trial focuses on patients with stable CHD and comorbid anxiety disorders, a group characterised by more pronounced autonomic imbalance and substantial pharmacological and comorbidity-related confounding. The central hypothesis is that closed-loop neurofeedback(NF) targeting the left DLPFC can, under experimentally induced stress, strengthen prefrontal control and thereby attenuate cardiac autonomic arousal, indexed by heart rate(HR), relative to a sham control condition. The study further postulates that inter-hemispheric synchronisation between left and right DLPFC will increase under real NF, reflecting a more coordinated prefrontal response pattern, and that changes in HR will be associated with, and partially mediated by, changes in left DLPFC activation and DLPFC inter-hemispheric coupling.

Study design and population The study is designed as a prospective, randomised, sham-controlled, parallel-group exploratory clinical trial. Adults with stable CHD and comorbid anxiety disorders are screened using predefined cardiac and psychiatric criteria. Key features include confirmed CHD(stress testing, prior myocardial infarction, or angiographic stenosis), DSM-5 anxiety disorder, right-handedness, and resting HR within a prespecified range; individuals with major arrhythmias, unstable angina, advanced heart failure, severe valvular disease, high-risk blood pressure profiles, or other unstable medical or psychiatric conditions are excluded. All participants must be free of psychotropic medications for at least one month prior to enrolment.

After providing informed consent and completing baseline cardiovascular and psychiatric assessments, eligible participants are randomly assigned in a 1:1 ratio to a real-neurofeedback group or a sham-neurofeedback group. Randomisation is stratified and concealed according to local procedures. Participants and outcome assessors are blinded to group allocation, whereas the operator running the neurofeedback software is aware of assignment but does not participate in outcome evaluation.