Neurocardiac Control in Major Depression

The presence of major depression, with or without pre-existing coronary artery disease, predicts increased mortality from myocardial infarction (MI) and sudden cardiac death (SCD). Decreased parasympathetic vagal outflow, especially in the presence of elevated cardiac sympathetic tone, has been proposed as a mechanism for the increased risk of SCD. Multiple lines of evidence suggests that fronto-limbic areas are actively engaged in the robust optimization of autonomic balance between sympathetic and parasympathetic cardiac outflow over a broad range of cognitive and physical demands. We propose that dysfunction of these forebrain neurocardiac networks in MDD mediates maladaptive cardiac autonomic control and the increased risk of cardiovascular mortality. In this model, neurocardiac control networks exhibit a systemic bias toward increased sympathetic relative to parasympathetic outflow. Increased amygdalar activity in MDD will promote this imbalance. Additionally, dysfunction in posterior orbitofrontal cortex (OFC) and ventral anterior cingulated cortex (ACC), areas associated with abnormal histopathological changes in MDD, will lead to reduced capacity for generating adaptive levels of cardioinhibitory, parasympathetic tone. This reduced capacity in depressives will be evidenced by abnormally large withdrawals of parasympathetic outflow, compared to healthy controls, as cognitive or physical demands increase. This dynamic model is potentially consistent with functional neuroimaging and post mortem histopathological findings in MDD and the knowledge gained through testing this protocol may ultimately elucidate how brain dysfunction in MDD mediates significantly increased clinical risk of spontaneous ventricular arrhythmias and sudden cardiac death. We propose to combine H (2) (15) O positron emission tomography (PET) and analysis of heart rate variability (HRV) in order to study in vivo the neural structures underlying normal forebrain control of cardiac autonomic function. We further aim to show whether regional functional abnormalities in amygdala, ventral anterior cingulate cortex, and orbitofrontal cortex-areas in which functional abnormalities have been identified in previous neuroimaging studies of major depressives-are associated with impaired modulation of cardiac autonomic function during major depression.