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

Abstract

Fear is prone to return following extinction that is the basis of exposure therapy for fear-related disorders. Manipulations that enhance the extinction process can be beneficial for treatment. Animal studies have shown that fasting or caloric restriction can enhance extinction and inhibit the return of fear. The present study examined the effects of fasting on fear acquisition, extinction, and the return of fear in humans. One hundred and twenty-five male participants were randomized into a fasting group and food group and exposed to a Pavlovian fear conditioning paradigm. Changes in plasma cortisol and ghrelin levels were examined using enzyme-linked immunosorbent assays. One-night fasting had no effect on fear acquisition but enhanced fear extinction retention and prevented the return of fear, and this effect persisted for at least 6 months. This procedure was also effective for remote fear memory. Plasma ghrelin levels were elevated after fasting and had a negative relationship with the fear response in spontaneous recovery test. However, overnight fasting did not affect cortisol levels. These findings indicate that fasting enhances extinction retention and prevents the return of fear, without influencing fear memory formation. We propose that this novel procedure may open new avenues for promoting extinction-based therapies for fear-related disorders.

The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders

“…In fear conditioning paradigms, caloric restriction and overnight fasting before extinction training were shown to enhance fear extinction and suppress return of fear in mice (Riddle et al, 2013;Huang et al, 2016;Verma et al, 2016), an effect that was abolished by administration of the GHSR antagonist D-Lys3 into the lateral amygdala (Huang et al, 2016). Interestingly, also in humans spontaneous recovery and reinstatement of fear were reduced after an overnight fast, which was correlated with ghrelin plasma levels (Shi et al, 2018). However, we could not confirm the extinction-promoting effect of overnight fasting using a weak extinction protocol and also found no difference between wild type and GHSR KO mice (Pierre et al, 2020).…”

“…To our knowledge, there are currently no studies published that directly investigated the effect of ghrelin-targeted interventions in stress-related psychiatric conditions. One study in healthy human participants found enhanced extinction memory retention and reduced return of fear following an overnight fast, which was negatively correlated with ghrelin plasma levels (Shi et al, 2018). Whether fasting may improve exposure-based psychotherapy outcomes in patients with anxiety disorders or PTSD and whether this would be associated with changes in plasma AG concentrations or brain GHSR function remains to be established.…”

Extent of food restriction affects probability but not delay‐based decision‐making

“…This behavioral difference at 0% suggests that components of decisionmaking, such as extinction learning and reward devaluation, may differ in this group. In humans, fasting promotes extinction learning in fear conditioning paradigms, suggesting that food-restriction may enhance extinction learning in our animals, and that this relationship may be dependent on the degree of restriction (Shi et al, 2018). Supporting this, in prior comparisons between weight-based and temporally restricted feeding schedules, animals that were less food restricted (in terms of body weight) were slower to extinguish behavior and subsequently devalue rewards (Baker et al, 2012).…”

Neuropeptides at the crossroad of fear and hunger: a special focus on neuropeptide Y

“…Along this line, activation of CRH neurons in the CeA may facilitate active responses toward external threats and suppress passive freezing behavior . Thus, the fear‐suppressing and extinction‐promoting effects of short‐term fasting, seen in Drosophila , mouse, and healthy human subjects, may be at least in part mediated by activation of specific CeL subpopulations that favors an active coping strategy (Fig. ).…”

“…Furthermore, the PVH receives afferents from limbic brain areas to integrate emotional stimuli with respective hormonal responses. Hunger promotes fear extinction and the HPA axis is a possible gateway linking hunger and fear. Peripherally released ghrelin activates central arcuate AgRP/NPY neurons and NPY may provide a link to the activation of PVH CRH neurons, triggering the activation of the HPA axis .…”