Abstract: The intimate connection between the brain and the heart was enunciated by Claude Bernard over 150 years ago. In our neurovisceral integration model we have tried to build on this pioneering work. In the present paper we further elaborate our model and update it with recent results. Specifically, we performed a meta-analysis of recent neuroimaging studies on the relationship between heart rate variability and regional cerebral blood flow. We identified a number of regions, including the amygdala and ventromedial prefrontal cortex, in which significant associations across studies were found. We further propose that the default response to uncertainty is the threat response and may be related to the well known negativity bias. Heart rate variability may provide an index of how strongly ‘top–down’ appraisals, mediated by cortical-subcortical pathways, shape brainstem activity and autonomic responses in the body. If the default response to uncertainty is the threat response, as we propose here, contextual information represented in ‘appraisal’ systems may be necessary to overcome this bias during daily life. Thus, HRV may serve as a proxy for ‘vertical integration’ of the brain mechanisms that guide flexible control over behavior with peripheral physiology, and as such provides an important window into understanding stress and health.