Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies

Abstract

Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the 'central autonomic-interoceptive network'. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations-a scarcely addressed dynamic in fMRI fear-conditioning studies-also suggests the existence of a coordinated brain response potentially underlying the 'safety signal' (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches.

Neural Substrates of Overgeneralized Conditioned Fear in PTSD

“…Thus, fear-related brain activations to CS+ found repeatedly in the amygdala (13), anterior insula (13,14), dorsomedial prefrontal cortex (13)(14)(15), dorsal anterior cingulate (14), inferior parietal lobule (14), and dorsolateral prefrontal cortex (16) are predicted to decrease as the presented GS diverge from CS+. Conversely, safetyrelated activations to CS-repeatedly found by human neuroimaging studies in the ventromedial prefrontal cortex (17), hippocampus (17), and precuneus (17) are predicted to gradually increase as the GS become less similar to CS+.…”

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…Mouse CSD resulted in excessive fear learning and memory of an aversive CS-US association, indicating that psychosocial stress induced generalized hyper-reactivity to aversion. Pavlovian fear learning-memory is an important translational readout for several reasons, including detailed knowledge of the neurobiology of adaptive fear learning-memory in healthy humans (Fullana et al, 2015) and mice (Duvarci and Pare, 2014;LeDoux, 2000;Wolff et al, 2014), and evidence for increased fear conditioning in MDD (Nissen et al, 2010) and GAD (Greenberg et al, 2013;Lissek et al, 2015). Repeated escitalopram reversed the increased fear expression, specifically, in CSD mice, indicating that the model has predictive validity.…”

“…A paradigm for the study of aversive-stimulus processing in humans and rodents is Pavlovian fear conditioning: repeated pairing of an initially neutral conditioned stimulus (CS) with an aversive unconditioned stimulus (US) results in the CS acquiring negative valence and eliciting emotional responses (Rescorla, 1988). In human and rodent, the US is usually mildmoderate electroshock (Fullana et al, 2015;Phelps and LeDoux, 2005), and visual and auditory CS are typically used in human and rodent, respectively (Fullana et al, 2015;Phelps and LeDoux, 2005). In humans, CS responsiveness is measured using skin conductance and subjective report (Fullana et al, 2015), and in rodents the defensive behaviour of complete 5 inactivity, or "freezing", is used (for review: (Blanchard et al, 2001;Maren and Quirk, 2004;Phelps and LeDoux, 2005)).…”

“…In human and rodent, the US is usually mildmoderate electroshock (Fullana et al, 2015;Phelps and LeDoux, 2005), and visual and auditory CS are typically used in human and rodent, respectively (Fullana et al, 2015;Phelps and LeDoux, 2005). In humans, CS responsiveness is measured using skin conductance and subjective report (Fullana et al, 2015), and in rodents the defensive behaviour of complete 5 inactivity, or "freezing", is used (for review: (Blanchard et al, 2001;Maren and Quirk, 2004;Phelps and LeDoux, 2005)). Rodent fear conditioned freezing provides a model system for investigating the neurobiology of negative valence processing, including CS-US learning, consolidation and recall of CS-US memory, and activation of conditioned freezing response (LeDoux, 2000;Rescorla, 1988;Wolff et al, 2014).…”

Effects of context preexposure and delay until anxiety retrieval on generalization of contextual anxiety

“…While the behavioral and neural mechanisms of fear or cued fear conditioning are fairly well examined in animal and humans (see Mechias et al 2010;Fullana et al 2016), studies on anxiety or contextual conditioning are less frequent and only recently have become the focus of human research (for recent reviews, see Davis et al 2010;Perusini and Fanselow 2015;Tovote et al 2015).…”