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A letter to the editor is presented in response to the article "Pharmacological enhancers of psychotherapeutical processes: the placebo problem," by B. Vervliet.

Meta-analyses indicate differences in Pavlovian fear responses between anxious and non-anxious individuals using electrodermal activity (EDA). Recent research, however, has cast doubt on whether these effects are robust to different analytic choices. Using the multiverse approach conceived by Steegen et al. (2016), we surveyed analytic choices typically implemented in clinical fear conditioning research by conducting 1240 analyses reflecting different choice permutations. Only 1.45% of our analyses produced theoretically congruent statistically significant effects, and the strength and direction of the estimated effects varied substantially across EDA processing methods. We conclude that EDA-estimated fear learning differences are vulnerable to researcher degrees of freedom and make recommendations regarding which analytical choices should be approached with a high degree of caution., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Safety learning involves associating stimuli with the absence of threats, enabling the inhibition of fear and anxiety. Despite growing interest in psychology, psychiatry, and neuroscience, safety learning lacks a formal consensus definition, leading to inconsistent methodologies and varied results. Conceptualized as a form of inhibitory learning (conditioned inhibition), safety learning can be understood through formal learning theories, such as the Rescorla-Wagner and Pearce-Hall models. This review aims to establish a principled conceptualization of 'Pavlovian safety learning', identifying cognitive mechanisms that generate safety and the boundary conditions that constrain it. Based on these observations, we define Pavlovian safety learning as an active associative process, where surprising threat-omission (safety prediction error) acts as a salient reinforcing event. Instead of producing merely neutral or nonaversive states, safety learning endows stimuli with active positive associations to 'safety'. The resulting stimulus-safety memories counteract the influence of fear memories, promoting fear regulation, positive affect, and relief. We critically analyze traditional criteria of conditioned inhibition for their relevance to safety and propose areas for future innovation. A principled concept of Pavlovian safety learning may reduce methodological inconsistencies, stimulate translational research, and facilitate a comprehensive understanding of an indispensable psychological construct., (© 2024. The Psychonomic Society, Inc.)

Short-chain fatty acids (SCFAs) are produced in the colon following bacterial fermentation of dietary fiber and are important microbiota-gut-brain messengers. However, their mechanistic role in modulating psychobiological processes that underlie the development of stress- and anxiety-related disorders is scarcely studied in humans. We have previously shown that colonic administration of a SCFA mixture (acetate, propionate, butyrate) lowers the cortisol response to stress in healthy participants, but does not impact fear conditioning and extinction. To disentangle the effects of the three main SCFAs, we examined whether butyrate alone would similarly modulate these psychobiological responses in a randomized, triple-blind, placebo-controlled intervention study in 71 healthy male participants (M age = 25.2, M BMI = 22.7 [n = 35 butyrate group, n = 36 placebo group]). Colon-delivery capsules with pH-dependent coating were used to administer 5.28 g of butyrate or placebo daily for one week. Butyrate administration significantly increased serum butyrate concentrations without modulating serum acetate or propionate, nor fecal SCFAs. Butyrate administration also significantly modulated fear memory at the subjective but not physiological levels. Contrary to expectations, no changes in subjective nor neuroendocrine responses to acute stress were evident between the treatment groups from pre- to post-intervention. We conclude that colonic butyrate administration alone is not sufficient to modulate psychobiological stress responses, unlike administration of a SCFA mixture. The influence of colonic and systemic butyrate on fear memory and the persistence of fear extinction should be further systematically investigated in future studies., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Relief, a pleasurable experience, is often triggered by successful threat avoidance. Although relief is regarded as the positive reinforcer for avoidance behavior, its rewarding nature remains to be demonstrated. In our study, 50 participants responded to cues associated with different magnitudes of monetary values or electrical stimuli. Successful responses to those cues resulted in monetary gains (i.e., rewards) or omissions of electrical stimulation (i.e., relief), followed by a pleasantness rating scale. We also measured physiological arousal via skin conductance. As expected, we found that for reward and relief similarly, higher magnitudes elicited more successful responses, higher pleasantness ratings, and higher skin conductance responses. Moreover, differential reward/relief response patterns predicted later choices between reward and relief cues. These findings indicate that relief induced by threat omissions is functionally equivalent to receiving a reward, confirming that relief is a positive reinforcer for threat avoidance behaviors, which provides a new theoretical perspective on the learning process of active threat avoidance. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background and Objectives: Early aversive experiences, which have been associated with elevated anxiety and intolerance of uncertainty (IUS), may contribute negatively to fear conditioning learning. The aim of the present study was to analyze the relation among individual differences in childhood maltreatment experiences, trait anxiety, and IUS in adulthood; and to determine how these variables could affect fear learning discrimination and avoidance generalization., Methods: We adapted an avoidance procedure in an online fear learning task. Two pictures of different lamp colors (CS+) were first associated with two aversive images (US), while a third color was not (CS-). Next, clicking a button during one CS + could effectively avoid the US (CS + av), but not during the other (CS + unav). Finally, avoidance generalization was tested to lamp colors that were between CS- and CS + av (safety dimension) and CS + av and CS + unav (avoidability dimension). With a sample of 67 participants, we measured ratings of relief, expectancy, and anxiety, as well as button presses and individual differences (STAI, IUS and MAES)., Results: Aversive early experiences were positively related to trait anxiety and intolerance of uncertainty. The results of the task further suggested that maltreatment experience contributes to be more attentive to aversive signals, which could be implicated in leading to difficulties in discrimination learning., Limitations: Online experiments implies some loss of control over subjects and environment that can threaten internal validity. Likewise, the commitment of participants may be low., Conclusions: Results suggest that early aversive experience and anxiety could contribute to the development of IUS, which likely contributes to the development of avoidance behavior., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: prolonged fasting influences threat and reward processing, two fundamental systems underpinning adaptive behaviors. In animals, overnight fasting sensitizes the mesolimbic-dopaminergic activity governing avoidance, reward, and fearextinction learning. Despite evidence that overnight fasting may also affect reward and fear learning in humans, effects on human avoidance learning have not been studied yet. Here, we examined the effects of 16 h-overnight fasting on instrumental avoidance and relief from threat omission. Methods: to this end, 50 healthy women were randomly assigned to a Fasting ( N = 25) or a Re-feeding group ( N = 25) and performed an Avoidance-Relief Task. Results: we found that fasting decreases unnecessary avoidance during signaled safety; this effect was mediated via a reduction in relief pleasantness during signaled absence of threat. A fasting-induced reduction in relief was also found during fear extinction learning. Discussion: we conclude that fasting optimizes avoidance and safety learning. Future studies should test whether these effects also hold for anxious individuals.

Avoiding pain-associated activities can prevent tissue damage. However, when avoidance spreads excessively (or overgeneralizes) to safe activities, it may culminate into chronic pain disability. Gaining insight into ways to reduce overgeneralization is therefore crucial. An important factor to consider in this is relief, as it reinforces avoidance behavior and therefore may be pivotal in making avoidance persist. The current study investigated whether experimentally induced positive affect can reduce generalization of pain-related avoidance and relief. We used a conditioning task in which participants (N = 50) learned that certain stimuli were followed by pain, while another was not. Subsequently, they learned an avoidance response that effectively omitted pain with one stimulus, but was ineffective with another. Next, one group of participants performed an exercise to induce positive affect, while another group performed a control exercise. During the critical generalization test, novel stimuli that were perceptually similar to the original stimuli were presented. Results showed that both avoidance and relief generalized to novel stimuli, thus replicating previous work. However, increasing positive affect did not reduce generalization of avoidance, nor relief., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Learning theories of depression propose that negative thinking is acquired through subsequent rewarding experiences and is often resistant to change even when it becomes associated with punishment. We examined whether this persistency of negative thinking is related to current and future levels of depressive symptoms among adolescents. Persistency of negative self-referent thinking was assessed by means of a decision-making task, namely the emotional reversal learning task. This task offers participants the choice between thinking about negative and positive self-related aspects. Their choice for negative self-referent thinking is initially rewarded but is later punished. Therefore, participants were expected to efficiently switch between negative and positive self-referent thinking, and to internally update their reward expectancy for these thinking options. Results showed that persistency of negative self-referent thinking was related to concurrent levels of depressive symptoms, replicating earlier findings in adults. However, persistency of negative thinking was unrelated to future levels of depressive symptoms. These findings suggest that adolescents with depressive symptoms tend to hold on to the belief that negative self-referent thinking has beneficial consequences, even when it is no longer being rewarded. This tendency should be seen as a concurrent feature of depression, as the predictive value is still in question., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Fear extinction is a topic of central importance in translational neuroscience. It integrates knowledge from various disciplines, including clinical psychology, experimental psychology, psychiatry, cellular and systems neuroscience, and pharmacology. The experimental phenomenon of extinction was first discovered by Ivan P. Pavlov more than 100 years ago and still forms the basis for investigating the psychological and physiological mechanisms that drive extinction of fear. Here, I present old and new ways to think about fear conditioning and extinction from a psychologist's point of view. Extinction is a simple phenomenon with a complex machinery. Enhancing the behavioral analysis of extinction is necessary to advance research in neighboring disciplines as well and to increase our chances to develop extinction enhancers that might further improve efficacy of extinction-based therapies to treat dysfunctional fears. For that purpose, I address a number of fundamental questions in this chapter to clarify psychological viewpoints on the process of fear extinction. What is extinction? What is an association? What is fear? What can we learn from fear extinction? My goal is to reinforce critical thinking about basic assumptions underlying fear extinction and to open up new avenues for further research., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Fear is an adaptive emotion that mobilizes defensive resources upon confrontation with danger. However, fear becomes maladaptive and can give rise to the development of clinical anxiety when it exceeds the degree of threat, generalizes broadly across stimuli and contexts, persists after the danger is gone or promotes excessive avoidance behaviour. Pavlovian fear conditioning has been the prime research instrument that has led to substantial progress in understanding the multi-faceted psychological and neurobiological mechanisms of fear in past decades. In this Perspective, we suggest that fruitful use of Pavlovian fear conditioning as a laboratory model of clinical anxiety requires moving beyond the study of fear acquisition to associated fear conditioning phenomena: fear extinction, generalization of conditioned fear and fearful avoidance. Understanding individual differences in each of these phenomena, not only in isolation but also in how they interact, will further strengthen the external validity of the fear conditioning model as a tool with which to study maladaptive fear as it manifests in clinical anxiety., Competing Interests: Competing interestsThe authors declare no competing interests., (© Springer Nature America, Inc. 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)