Colonic butyrate administration modulates fear memory but not the acute stress response in men: A randomized, triple-blind, placebo-controlled trial.

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 (Mage = 25.2, MBMI = 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.

What a relief! The pleasure of threat avoidance.

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).

Fear Extinction as a Psychologist Views It.

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.

Relation among, trait anxiety, intolerance to uncertainty and early maltreatment experiences on fear discrimination learning and avoidance generalization online task.

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.

The effect of experimentally induced positive affect on the generalization of pain-related avoidance and relief.

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.

Understanding clinical fear and anxiety through the lens of human fear conditioning.

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.

Depressive symptoms and persistent negative self-referent thinking among adolescents: A learning account.

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.

Overnight fasting affects avoidance learning and relief.

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.

No joy - why bother? Higher anhedonia relates to reduced pleasure from and motivation for threat avoidance.

Anhedonia impairs various components of the pleasure cycle, including wanting, liking, and the learning of pleasure-related associations. While successfully controlling threats might be inherently pleasurable, it remains unclear whether anhedonia affects this form of pleasure as well. With aversive pictures as threats, we conducted an online study ( N = 200) to investigate the role of anhedonia during active avoidance learning process. Participants first learned cue-threat associations for different cues (threat vs. safety cues). In a subsequent avoidance learning phase, these cues signaled either avoidable, unavoidable, or no threat; participants could perform avoidance responses to prevent the upcoming threats during those cue presentations. Subjective relief pleasantness was measured after each threat omission. We found that higher trait anticipatory and consummatory anhedonia were both associated with lower relief pleasantness. Higher trait anticipatory anhedonia was also associated with fewer avoidance attempts. Since reduced threat-controlling behavior is reminiscent of a learned-helplessness state, the current results contribute to a better understanding of the connections between anhedonia and learned helplessness that have mostly been studied separately in the context of mood disturbance.

The role of relief, perceived control, and prospective intolerance of uncertainty in excessive avoidance in uncertain-threat environments.

Excessive avoidance is a key feature of pathological anxiety. However, the precise mechanisms underlying the development of excessive avoidance are still unknown. In the present study, we tested the hypothesis that excessive avoidance, especially in individuals with high Intolerance of Uncertainty (IU) is aimed at distress reduction via the enhancement of subjective perceived control in uncertain-threat environments. In our experiment, participants learned to avoid an uncertain aversive sound through a discriminated free operant procedure. In a later test phase in extinction, we manipulated the amount of avoidance responses available per trial by creating a limited and an unrestricted response condition. Nonetheless, the aversive sound could be effectively avoided in both conditions. We measured response frequency, avoidance confidence ratings and anxiety-predisposing traits such as intolerance of uncertainty, trait anxiety and distress tolerance. The degree of distress suffered during trials was inferred from post-trial relief ratings that were requested after trials in which the aversive sound had been omitted. In the avoidance acquisition phase, we found a positive association between prospective intolerance of uncertainty (P-IU) and the decline rate of distress. This relationship was not significant, however, when inhibitory intolerance of uncertainty (I-IU) was controlled for. At test, we found that the increase in avoidance responses led to distress reduction through the enhancement of avoidance confidence. Finally, we found a significant modulating role of P-IU in the effect of response limit on distress reduction that lends further support to our hypothesis. Specifically, P-IU was positively associated with the effect of response limit on distress. However, such modulating role was not significant when controlling for trait anxiety or I-IU.

Extruded Wheat Bran Consumption Increases Serum Short-Chain Fatty Acids but Does Not Modulate Psychobiological Functions in Healthy Men: A Randomized, Placebo-Controlled Trial.

Background: Incorporation of wheat bran (WB) into food products increases intake of dietary fiber, which has been associated with improved mood and cognition and a lower risk for psychiatric disorders such as depression, with short-chain fatty acids (SCFAs) as candidate mediators of these effects. Modifying WB using extrusion cooking increases SCFA production in vitro relative to unmodified WB. Objective: The aim of this study was to evaluate the effects of extruded WB on psychobiological functioning and the mediating role of SCFAs. Methods: In a randomized, triple-blind, placebo-controlled trial, 69 healthy male participants consumed 55 g of breakfast cereal containing either extruded WB or placebo daily for 28 days. At pre- and post-intervention visits, the cortisol response to experimentally induced stress was measured as a primary outcome. In addition, serum SCFAs and brain-derived neurotrophic factors were quantified as potential mediators. Secondary psychobiological outcomes included subjective stress responses, responses to experimentally induced fear, cortisol awakening response, heart rate variability, and retrospective subjective mood ratings. Intestinal permeability, fecal SCFAs, and stool consistency were measured as secondary biological outcomes. Results: Extruded WB increased serum acetate and butyrate (p < 0.05). None of the primary or secondary outcomes were affected by the intervention. Participants who consumed a placebo exhibited an increase in the percentage of fecal dry weight but did not report increased constipation. Despite these statistically significant effects, these changes were small in magnitude. Conclusions: Extruded WB consumption increased serum short-chain fatty acids but did not modulate psychobiological functions in healthy men. Effective modulation of psychobiological functions may require greater increases in SCFAs than those achieved following extruded WB consumption. Rather than attempting to induce health benefits with a single fiber-rich food, combinations of different fibers, particularly highly fermentable ones, might be needed to further increase SCFA production and uptake in the systemic circulation to observe an effect on psychobiological processes.

More engagement in inefficient avoidance through partial reinforcement.

BACKGROUND AND OBJECTIVES: In anxiety-related disorders, excessive avoidance often coexists with an impaired sense of control over external threats. In contrast, lab studies have shown that avoidance responding increase with higher objective controllability over threat, accompanied with more confidence in the effectiveness of the avoidance response. One reason for this divergence could be that those lab studies are overly simplistic with a single, avoidable threat. METHODS: We conducted an experiment that additionally included a completely uncontrollable threat, and we manipulated the reinforcement rate of the avoidance response to the (semi-)controllable threat (75% versus 100%). RESULTS: The 100% group showed increased avoidance to the controllable threat and decreased avoidance to the unavoidable threat over learning. Interestingly, compared to the 100% group, the 75% group displayed less confidence in their avoidance to the controllable threat and they avoided the uncontrollable threat more often. LIMITATIONS: Only two reinforcement rates of effective avoidance were included, which may limit the generalizability of the current findings. Perceived control was not directly measured. CONCLUSIONS: Lower reinforcement rates create ambiguity between effective and ineffective situations of avoidance, which engenders generalization of unpredictability from effective to ineffective situation, thereby driving up ineffective avoidance rates. Partially reinforced effective avoidance responses and elevated ineffective avoidance responses together lead to more exposure to uncontrollable threat, weakening the sense of control over the threat, which could further increase avoidance behaviors. Controllability is often overlooked in avoidance research but can be key to understanding the development of maladaptive avoidance behaviors.

Cortico-Striatal Activity Characterizes Human Safety Learning via Pavlovian Conditioned Inhibition.

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation (PFDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC compared with the standard safety signal, whereas the latter evoked greater activation of the ventromedial PFC, posterior cingulate, and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of "stimulus-safety" associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.SIGNIFICANCE STATEMENT Identifying safety is critical for maintaining adaptive levels of anxiety, but the neural mechanisms of human safety learning remain unclear. Using 7 Tesla fMRI, we compared learning-related brain activity for a conditioned inhibitor, which actively predicted threat omission, and a standard safety signal (CS-), which was passively unpaired with threat. The inhibitor engaged an extended circuitry primarily featuring the dorsal striatum, along with thalamic, midbrain, and premotor/PFC regions. The CS- exclusively involved cortical safety-related regions observed in basic safety conditioning, such as the vmPFC. These findings extend current models to include learning-specific mechanisms for encoding stimulus-safety associations, which might be distinguished from expression-related cortical mechanisms. These insights may suggest novel avenues for targeting dysfunctional safety learning in psychopathology.

Optimizing exposure therapy with an inhibitory retrieval approach and the OptEx Nexus.

Research from recent decades has highlighted the distinction between excitatory and inhibitory Pavlovian learning mechanisms. Based on this distinction, state-of-the-art exposure therapy for anxiety disorders emphasizes inhibitory learning and retrieval as its primary mechanism for long-term reduction in fear, anxiety, and avoidance. Seven years ago, we (Craske, et al., 2014) summarized exposure therapy from an inhibitory learning approach, focusing on eight exposure optimization strategies. Here, we update this model based on recent work and describe how to conduct exposure therapy from an inhibitory retrieval approach and encourage further empirical investigation of its basic premises. To this end, we guide the reader in the use of the OptEx Nexus: a clinician's tool for conducting exposure therapy from an inhibitory retrieval approach. We categorize exposure strategies as fundamental (expectancy violation, attention to feared stimulus/situation, removal of safety signals, and mental rehearsal after exposure), advanced (deepened extinction, occasional reinforced extinction), and promoting generalization of learning (retrieval cues, multiple contexts, stimulus variability, positive affect). We additionally discuss extinction learning with distal future feared outcomes, the role of avoidance, and alternative models/approaches to exposure therapy, including counterconditioning, novelty-enhanced extinction, latent cause models, and reconsolidation. Lastly, we illustrate clinical implementation via vignettes of exposure therapy from an inhibitory retrieval approach (see Supplemental materials).

When the mind says one thing, but the HPA axis says another: Lack of coherence between subjective and neuroendocrine stress response trajectories in healthy men.

Psychological stress triggers the release of cortisol following the activation of the hypothalamic-pituitary-adrenal (HPA) axis and elicits concomitant subjective responses. Coherence among the stress response systems is theoretically expected, presumably to optimize the organism's response to environmental challenges, but has received little empirical support possibly due to the assumption of linear associations. The present study examined the associations between cortisol responses to the Maastricht Acute Stress Test (MAST) and concomitant subjective stress responses as well as mood states over the past weeks in 133 healthy men. Latent class growth analysis (LCGA) was applied on individual cortisol and subjective stress responses to identify homogeneous response trajectories within the larger heterogeneous population and enable testing non-linear relationships while retaining the temporal resolution of the stress responses. LCGA revealed four latent cortisol response classes, labeled as mild responders (n = 15), moderately-low responders (n = 46), moderately-high responders (n = 48), and hyper responders (n = 24). These latent classes were not associated with concomitant subjective stress responses. Similarly, the three distinct latent classes capturing the variability in subjective stress responses were also not associated with concomitant cortisol responses. Experiencing higher levels of stress over the previous weeks, however, increased the likelihood of exhibiting a hyper cortisol stress response profile. Positive and negative affective states, and anxious and depressive symptomology over the previous weeks were not associated with cortisol response trajectories. Contrary to previous findings supporting a quadratic association in healthy females, our results do not support the response coherence hypothesis in healthy males subjected to the MAST, but suggest that recent levels of perceived stress may influence the cortisol response to acute stress.

Perceptual sensitivity to sensory and affective aspects of dyspnea: Test-retest reliability and effects of fear of suffocation.

Perceptual sensitivity for dyspnea (i.e. breathlessness) is often quantified using the slope of magnitude estimations plotted against the physical stimulus intensities of respiratory loads. This study investigated whether this slope and its stability varies as a function of (1) affective versus sensory aspects of dyspnea, and (2) interindividual differences in Fear of Suffocation. Eighty-three healthy women performed a load magnitude estimation task twice one week apart. Resistive loads of increasing magnitude (0-2.4-5-7.4-12.4-20 cmH20/l/s) were repeatedly presented for a single flow-targeted inspiration. One group rated the intensity of loads, another their unpleasantness. Neither slopes nor intercepts differed between sensory versus affective aspects of dyspnea. Intercepts were lower in the second compared to the first session. Fear of Suffocation was associated with flatter slopes. Test-retest reliabilities were low to moderate suggesting that perceptual sensitivity to dyspnea is less stable than commonly assumed.

Fear learning, avoidance, and generalization are more context-dependent for adults than adolescents.

This study examined developmental differences in contextual and perceptual generalization of fear and avoidance learning. Adults (N = 39) and adolescents (N = 44) completed differential fear acquisition wherein each conditional stimulus (CS) appeared in a background context. In the dangerous context, one stimulus (CS+) predicted an aversive sound, and the other stimulus (CS-) did not. In the safe context, the aversive sound was never administered with either CS. During fear generalization, participants were presented with three generalization stimuli (GSs), ranging on a perceptual continuum from threat to safety stimuli, in both contexts. Participants then completed avoidance conditioning and avoidance generalization phases, allowing them to actively avoid the upcoming aversive sound by pressing an avoidance button. Developmental differences emerged in threat perception, physiological arousal, avoidance behavior, and eye movements during contextual fear learning and generalization. Adolescents showed less discrimination between stimuli and contexts than adults, resulting primarily from their elevated fear responses to safety and generalized stimuli. Developmental differences in fear learning should be further explored in future research, as they could explain why adolescence is a sensitive developmental period for anxiety.

Experimental models in psychopathology research: The relation between Research Domain Criteria and Experimental Psychopathology.

Experimental Psychopathology (EPP) and the Research Domain Criteria (RDoC) are research approaches that have developed in parallel, providing inter-related yet different scientific frameworks to investigate psychopathology at the intersection of fundamental and applied research. Here we address the overlap and differences between RDoC and EPP, and the challenges that both approaches face. Although overlap between EPP and RDoC can be clearly observed, each approach has its own unique strengths and weaknesses. These aspects will be illustrated by examples with respect to fear conditioning, an experimental procedure that has played a central role in both EPP and RDoC. We see much potential in boosting psychopathology research by combining the strengths of these two approaches.

Corrigendum: Low-Cost Avoidance Behaviors are Resistant to Fear Extinction in Humans.

[This corrects the article DOI: 10.3389/fnbeh.2015.00351.].