From Fear to Safety and Back: Reversal of Fear in the Human Brain

Abstract

Fear learning is a rapid and persistent process that promotes defense against threats and reduces the need to relearn about danger. However, it is also important to flexibly readjust fear behavior when circumstances change. Indeed, a failure to adjust to changing conditions may contribute to anxiety disorders. A central, yet neglected aspect of fear modulation is the ability to flexibly shift fear responses from one stimulus to another if a once-threatening stimulus becomes safe or a once-safe stimulus becomes threatening. In these situations, the inhibition of fear and the development of fear reactions co-occur but are directed at different targets, requiring accurate responding under continuous stress. To date, research on fear modulation has focused mainly on the shift from fear to safety by using paradigms such as extinction, resulting in a reduction of fear. The aim of the present study was to track the dynamic shifts from fear to safety and from safety to fear when these transitions occur simultaneously. We used functional neuroimaging in conjunction with a fear-conditioning reversal paradigm. Our results reveal a unique dissociation within the ventromedial prefrontal cortex between a safe stimulus that previously predicted danger and a "naive" safe stimulus. We show that amygdala and striatal responses tracked the fear-predictive stimuli, flexibly flipping their responses from one predictive stimulus to another. Moreover, prediction errors associated with reversal learning correlated with striatal activation. These results elucidate how fear is readjusted to appropriately track environmental changes, and the brain mechanisms underlying the flexible control of fear.

Learning not to Fear: Neural Correlates of Learned Safety

“…Similarly, another imaging study showed that conditioned subjects, who had learned to associate one cue with a mild shock and a second cue (safety) with no shock, showed higher amygdala activation during the presentation of the aversive cue, whereas greater striatal activation was found in the presence of the safety cue. When the reinforcement contingencies were reversed, the neural activity pattern in response to the previous fear cue shifted from the amygdala to areas of the ventral prefrontal cortices and the striatum (Schiller et al, 2008). These results are consistent with specific and distinctive neural circuitries subserving learned safety, which involve at least the LA, the striatum, and regions of the PFC (Figure 4).…”

“…As is the case for experimental research with animal models, learned safety is only beginning to be explored in humans (Grillon and Ameli, 2001;Grillon et al, 1994b;Jovanovic et al, 2010Jovanovic et al, , 2012bLissek et al, 2009;Pollak et al, 2010b;Schiller et al, 2008). Already in the 1990s, pioneering work by Christian Grillon and Michael Davis firstly described the translational potential of learned safety by examining the impact of safety signals on human anxiety and found that safety signals were able to reduce anticipatory anxiety as revealed by a FPS paradigm (Grillon et al, 1994b).…”

Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits

“…However, the extension of our findings and findings like these to the clinic is premature. Although some studies in humans suggest that immediate behavioral intervention (e.g., extinction) may dampen fear and drug-seeking behavior (Schiller et al 2008;Xue et al 2012), there are human studies that indicate that this approach may have little effect or even enhance memory expression (Karpicke and Roediger 2008;Soeter and Kindt 2011;Wichert et al 2011;Potts and Shanks 2012;Kindt and Soeter 2013). Particularly problematic for clinical applications are rodent and preclinical studies like ours suggesting that across a variety of conditions an immediate extinction experience may actually prevent the elimination or weakening of the fear response and promote its persistent expression (Morris et al 2005;Chan et al 2010;Kim et al 2010).…”

“…Several recent studies of memory have asked whether extinction under certain conditions can erase, rather than just suppress, previously established memories (Myers et al 2006;Norrholm et al 2008;Schiller et al 2008;Monfils et al 2009). One popular idea is that extinction during periods of memory lability, which is thought to occur soon after acquisition or retrieval ("immediate extinction"), may permanently displace the original fear memory with a new, safe memory.…”

The exclusive induction of extinction is gated by BDNF

“…Studies with fear conditioning to a discrete cue identified several factors that affect the resistance of extinction to recovery. These include the interval between conditioning and extinction (Myers et al 2006;Woods and Bouton 2008;Huff et al 2009; but see Alvarez et al 2007;Schiller et al 2008;Archbold et al 2010), the interval between extinction and test (Bouton 1993(Bouton , 2004Quirk 2002), the level of fear behavior at extinction (Maren and Chang 2006), and the number and pattern of nonreinforced trails (Cain et al 2003;Urcelay et al 2009). These factors would be expected to interact with each other such that the precise experimental conditions used by independent laboratories would differentially reveal recovery of the cued fear responses.…”