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.

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.

Perceptual errors are related to shifts in generalization of conditioned responding.

Studies of perceptual generalization have recently demonstrated a close relationship between stimulus perception and conditioned responding, suggesting that incorrect stimulus perception might account for certain characteristics of generalization gradients. In this study, we investigated whether common phenomena, such as the area and peak shift in conditioned responding, relate to perceptual errors. After a differential conditioning procedure, in which one circle was paired with the presentation of an aversive picture whereas a different-sized circle was not, we combined a generalization test with a three-alternative forced-choice perceptual categorization task where participants had to indicate on every trial whether the presented circle was one of the two circles from the conditioning phase or a different one, after which US-expectancy ratings were collected. The typical peak and area shift were observed when conditioned responses were plotted on a physical dimension. However, when stimulus perception was incorporated generalization gradients diverged from the typical gradient. Both the area and peak shift largely disappeared when accounting for perceptual errors. These findings demonstrate the need to incorporate perceptual mechanisms in associative models.

Paul Eelen: Reflections on Life and Work.

This manuscript is part of a special issue to commemorate professor Paul Eelen, who passed away on August 21, 2016. Paul was a clinically oriented scientist, for whom learning principles (Pavlovian or operant) were more than salivary responses and lever presses. His expertise in learning psychology and his enthusiasm to translate this knowledge to clinical practice inspired many inside and outside academia. Several of his original writings were in the Dutch language. Instead of editing a special issue with contributions of colleagues and friends, we decided to translate a selection of his manuscripts to English to allow wide access to his original insights and opinions. Even though the manuscripts were written more than two decades ago, their content is surprisingly contemporary. This introductory article presents a reflection on Paul's career and legacy and introduces the selected manuscripts that are part of this special issue.

Human ventromedial prefrontal cortex and the positive affective processing of safety signals.

Human functional magnetic resonance imaging (fMRI) studies suggest that the ventromedial prefrontal cortex (vmPFC) contributes to the learned discrimination of threat and safety signals, although its precise contribution to these processes remains unclear. One hypothesis is that the vmPFC supports the positive affective processing of safety signals linked to their implicit stress-relieving properties. We set out to test this hypothesis and to examine the specificity of vmPFC responses to safety signal processing versus its high level of 'default mode' activity. Sixty participants completed an fMRI conditioning task that involved the generation of a conditioned threat (CS+) and safety (CS-) signal following the completion of a pre-conditioning baseline. Confirming past findings, activation of the vmPFC and other midline cortical and parietal areas - broadly resembling the default mode network - robustly discriminated between the CS- and CS+. However, when adjusting for this network's characteristic 'baseline' activity, only a subset of regions, including the vmPFC, was activated by the CS-. Regional selectivity for safety signal processing was confirmed by demonstrating a significant correlation between the magnitude of vmPFC responses and self-rated positive affect evoked by the CS-. Taken together, our current findings confirm a link between human vmPFC activity and the positive affective processing of safety signals. We discuss these findings with regards a broader model of human vmPFC function and its suggested higher-order contribution to emotionally adaptive behavior.

Conditioned Subjective Responses to Socially Relevant Stimuli in Social Anxiety Disorder and Subclinical Social Anxiety.

UNLABELLED: Although enhanced fear conditioning has been implicated in the origins of social anxiety disorder (SAD), laboratory evidence in support of this association is limited. Using a paradigm employing socially relevant unconditioned stimuli, we conducted two separate studies to asses fear conditioning in individuals with SAD and non-clinical individuals with high social anxiety (subclinical social anxiety [SSA]). They were compared with age-matched and gender-matched individuals with another anxiety disorder (panic disorder with agoraphobia) and healthy controls (Study 1) and with individuals with low social anxiety (Study 2). Contrary to our expectations, in both studies, self-report measures (ratings of anxiety, unpleasantness and arousal to the conditioned stimuli) of fear conditioning failed to discriminate between SAD or SSA and the other participant groups. Our results suggest that enhanced fear conditioning does not play a major role in pathological social anxiety. KEY PRACTITIONER MESSAGE: We used a social conditioning paradigm to study fear conditioning in clinical and subclinical social anxiety. We found no evidence of enhanced fear conditioning in social anxiety individuals. Enhanced fear conditioning may not be a hallmark of pathological social anxiety.

Fear generalization in humans: impact of feature learning on conditioning and extinction.

Little is known about the role of discrete stimulus features in the regulation of fear. This study examined the effects of feature learning on the acquisition and extinction of fear conditioning. Human participants were fear conditioned to a yellow triangle (CS+) using an electrical shock. We manipulated feature learning through differential conditioning. The nonconditioned control stimulus (CS-) was a red triangle in one group (Color-Relevant), but a yellow circle in the other group (Shape-Relevant). Next, two generalization stimuli were tested that shared the shape- or color-feature with the CS+ (a blue triangle and a yellow square). Online shock-expectancy ratings and skin conductance responding showed that the CS- determined the pattern of fear generalization: the same-color stimulus elicited more fear in Group Color-Relevant, versus the same-shape stimulus in group Shape-Relevant. Furthermore, extinguishing these two generalization stimuli had no detectable effect on fear of the CS+. These results show that fear generalization is influenced by feature learning through differential conditioning, and that exposures to different features of a stimulus are not sufficient to extinguish fear of that stimulus as a whole.

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).

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.

Using electrodermal activity to estimate fear learning differences in anxiety: A multiverse analysis.

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.

Fear extinction and relapse: state of the art.

Exposure-based treatments for clinical anxiety generally are very effective, but relapse is not uncommon. Likewise, laboratory studies have shown that conditioned fears are easy to extinguish, but they recover easily. This analogy is striking, and numerous fear extinction studies have been published that highlight the processes responsible for the extinction and return of acquired fears. This review examines and integrates the most important results from animal and human work. Overall, the results suggest that fear extinction is relatively easy to "learn" but difficult to "remember." It follows that treatments will benefit from an enhanced focus on the long-term retrieval of fear extinction. We review the available studies on the prevention of return of fear and the prospects of weakening fear memories forever. We show that the behavioral principles outlined in learning theory provide a continuous inspiration for preclinical (neurobiological) and clinical research on the extinction and return of fear.

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.

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.

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.

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.

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.

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.

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).