Neural Underpinnings of Cortisol Effects on Fear Extinction

Abstract

Extinction of conditioned fear embodies a crucial mechanism incorporated in exposure therapy. Clinical studies demonstrated that application of the stress hormone cortisol before exposure sessions facilitates exposure success, but the underlying neural correlates remain unknown. Context- and stimulus-dependent cortisol effects on extinction learning will be characterized in this study and tested in the extinction and in a new context. Forty healthy men participated in a 3-day fear conditioning experiment with fear acquisition in context A (day 1), extinction training in context B (day 2), and recall in context B and a new context C one week later (day 3). Hydrocortisone (30 mg) or placebo was given before extinction training. Blood-oxygen-level-dependent responses and skin conductance responses (SCRs) served as dependent measures. At the beginning of extinction training, cortisol reduced conditioned SCRs, diminished activation of the amygdala-hippocampal complex, and enhanced functional connectivity of the anterior parahippocampal gyrus with the ventromedial prefrontal cortex (vmPFC). After one week, the cortisol group showed increased hippocampal activation and connectivity to the vmPFC toward an extinguished stimulus and reduced insula activation toward a nonextinguished stimulus in the extinction context. However, this inhibitory cortisol effect did not extend to the new context. Taken together, cortisol reduced fear recall at the beginning of extinction and facilitated the consolidation of the extinction memory as evidenced by an inhibitory activation pattern one week later. The stress hormone exerted a critical impact on the amygdala-hippocampus-vmPFC network underlying fear and extinction memories. However, cortisol did not attenuate the context dependency of extinction.

Fasting enhances extinction retention and prevents the return of fear in humans

“…Previous studies showed that cortisol reduces fear recall and facilitates the consolidation of extinction memory in both animals and humans 60 , 61 . We also investigated whether fasting induces a stress response that influences extinction memory.…”

Stress modulation of fear and extinction in psychopathology and treatment

“…We found that exposure to stress or cortisol administration before extinction learning promotes extinction memory consolidation in a context-independent way (Meir Drexler et al, 2017; but see: Merz et al, 2018), making extinction memory more resistant to relapse after context change (see similar GCs-related contextual impairments in other tasks: McGlade et al, 2019;Schwabe et al, 2009;van Ast et al, 2013). In contrast, exposure to stress/cortisol after extinction leads to an enhanced, but context-dependent, extinction memory trace , making extinction retrieval more likely, but only in the context in which it had been learned (see GCs-related context-dependency in other tasks: van Ast et al, 2013).…”

“…In line with evidence from previous works on animals and humans (Milad and Quirk, 2012), our findings suggest that the ventromedial prefrontal cortex (vmPFC) and the hippocampus are activated and determine, based on the given context, whether or not extinction memory is expressed under nonstressful conditions. However, if cortisol was administered before extinction learning, activity of the hippocampus and its functional connectivity to the vmPFC increases in a later retrieval task, leading to enhanced extinction retrieval and thus reduced fear (Merz et al, 2018). In contrast, exposure to cortisol before the retrieval task itself suppresses vmPFC activation and its connectivity with the parahippocampal gyrus, enhances activation of the amygdala, and leads to impaired extinction retrieval and thus enhanced fear (Kinner et al, 2016(Kinner et al, , 2018.…”

Glucocorticoid-induced enhancement of extinction—from animal models to clinical trials

“…Thus, from a clinical perspective, stress induction or cortisol administration should occur before extinction training in order to create a stronger and less context-dependent extinction memory trace. In a recent pharmacological functional MRI (fMRI) study (Merz et al 2018 ), cortisol administered before extinction diminished activation of the amygdala-hippocampal neural network at the beginning of extinction and enhanced functional connectivity of the anterior parahippocampal gyrus with the ventromedial prefrontal cortex (vmPFC), a brain region crucially involved in extinction processes (Milad and Quirk 2002 ). These network alterations may underlie the blocking effects of cortisol on the retrieval of the initial fear memory and its combination with the beneficial effects on the consolidation of fear extinction memory (Nakataki et al 2017 ).…”