Neuropsychobiology of fear-induced bradycardia in humans: progress and pitfalls

Abstract

In the last century, the paradigm of fear conditioning has greatly evolved in a variety of scientific fields. The techniques, protocols, and analysis methods now most used have undergone a progressive development, theoretical and technological, improving the quality of scientific productions. Fear-induced bradycardia is among these techniques and represents the temporary deceleration of heart beats in response to negative outcomes. However, it has often been used as a secondary measure to assess defensive responding to threat, along other more popular techniques. In this review, we aim at paving the road for its employment as an additional tool in fear conditioning experiments in humans. After an overview of the studies carried out throughout the last century, we describe more recent evidence up to the most contemporary research insights. Lastly, we provide some guidelines concerning the best practices to adopt in human fear conditioning studies which aim to investigate fear-induced bradycardia.

Fig. 1. Psychophysiological conditioned responses.

Fear acquisition is achieved by presenting a neutral stimulus (conditioned stimulus, CS+) with a negative consequence, like a shock to the wrist (unconditioned stimulus, US). This causes fear learning to take place, which manifests the development of conditioned responses to the conditioned stimulus (CS+), such as increased skin conductance response and fear-induced bradycardia, even in the absence of a threatening outcome - such as during extinction. During extinction training, however, repeated presentations of CSs without painful sensations bring physiological responses back to baseline levels. Administering the US after the extinction phase, however, triggers a reinstatement effect, that is, the CS+ typically elicits physiological activation again. The figure was created using BioRender.com.

Fig. 2. Schematic representation of heart period variations following fear conditioning.

A Heart period is measured by calculating the distance in milliseconds between consecutive R peaks. B Average cardiac responses to CS+ and CS− during fear acquisition training. Starting at the time of CS onset, the classic pattern of early deceleration (D1), acceleration (A1), and late deceleration (D2) can be observed, which persists even after the acquisition training phase, when the CS+ is presented without the US (e.g., during extinction training). The vertical dashed line represents the time of US administration, the horizontal dashed line represents the baseline. C When facing a threatening event, a complex interplay between the central and the autonomic nervous systems is set in motion. Under normal circumstances, environmental cues are identified by the prefrontal cortex (PFC), which inhibits sympathoexcitatory networks. Moreover, PFC control over subcortical structures is crucial for HRV regulation [113]. When facing threat, however, these circuits become disinhibited, which in turn allow the emergence of fear responses [139]. The prefrontal cortex and the amygdala govern parasympathetic functioning by regulating the dorsal nucleus of the vagus nerve, innervating the vagus nerve itself, and ending with the sinoatrial node of the heart, whereby fear-induced bradycardia is engendered. This reflects the connections between the central and peripheral nervous systems that reach the heart. The figure was created using BioRender.com.

Fig. 3. Heart period responses from the experiments by Castegnetti et al. [31].

Each experiment was designed differently with the aim of validating a psychophysiological model that can discriminate between CS+ and CS− based on heart period responses. In fact, in both experiments 1 and 3, heart period responses had a better predicting validity than skin conductance responses, suggesting the feasibility of the model. In each of these graphs, the classic pattern of D1, A, and D2, more pronounced in the case of CS+ presentation compared to CS-, can be observed. This image was adapted from Figure 3 from Castegnetti et al. [31], Psychophysiology. The figure was created using BioRender.com.

Fig. 4. HP responses from Battaglia et al. [104] experiment.

Beyond the classical deceleration and acceleration pattern, two new components have been highlighted, a second acceleration (A2) and a third deceleration (D3), bringing HR back to baseline level. The yellow lines represent, from left to right, the time of CS onset and offset, while the purple line represents the time of US administration. As an important note, the onset of the D2 component is concomitant with the time of US administration. This image was adapted from Battaglia et al. [104], Psychophysiology. The figure was created using BioRender.com.