No harmful effect of propranolol administered prior to fear memory extinction in rats and humans.

Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.

A history of avoidance does not impact extinction learning in male rats.

Pervasive avoidance is one of the central symptoms of all anxiety-related disorders. In treatment, avoidance behaviors are typically discouraged because they are assumed to maintain anxiety. Yet, it is not clear if engaging in avoidance is always detrimental. In this study, we used a platform-mediated avoidance task to investigate the influence of avoidance history on extinction learning in male rats. Our results show that having the opportunity to avoid during fear acquisition training does not significantly influence the extinction of auditory-cued fear in rats subjected to this platform-mediated avoidance procedure, which constitutes a realistic approach/avoidance conflict. This holds true irrespective of whether or not avoidance was possible during the extinction phase. This suggests that imposing a realistic cost on avoidance behavior prevents the adverse effects that avoidance has been claimed to have on extinction. However, avoidance does not appear to have clear positive effects on extinction learning nor on retention either.

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).

Instrumental learning and behavioral persistence in children with attention-deficit/hyperactivity-disorder: does reinforcement frequency matter?

BACKGROUND: Prominent theoretical accounts of attention-deficit/hyperactivity-disorder (ADHD) hypothesize that reinforcement learning deficits underlie symptoms of ADHD. The Dynamic Developmental Theory and the Dopamine Transfer Deficit hypothesis assume impairments in both the acquisition and extinction of behavior, especially when learning occurs under partial (non-continuous) reinforcement, and subsequently the Partial Reinforcement Extinction Effect (PREE). Few studies have evaluated instrumental learning in ADHD and the results are inconsistent. The current study investigates instrumental learning under partial and continuous reinforcement schedules and subsequent behavioral persistence when reinforcement is withheld (extinction) in children with and without ADHD. METHODS: Large well-defined samples of children with ADHD (n = 93) and typically developing (TD) children (n = 73) completed a simple instrumental learning task. The children completed acquisition under continuous (100%) or partial (20%) reinforcement, followed by a 4-min extinction phase. Two-way (diagnosis by condition) ANOVAs evaluated responses needed to reach the learning criterion during acquisition, and target and total responses during extinction. RESULTS: Children with ADHD required more trials to reach criterion compared to TD children under both continuous and partial reinforcement. After partial reinforcement, children with ADHD executed fewer target responses during extinction than TD children. Children with ADHD executed more responses than TD children during extinction, irrespective of learning condition. CONCLUSIONS: The findings demonstrate general difficulties in instrumental learning in ADHD, that is, slower learning irrespective of reinforcement schedule. They also show faster extinction following learning under partial reinforcement in those with ADHD, that is, a diminished PREE. Children with ADHD executed more responses during extinction. Results are theoretically important, with clinical implications for understanding and managing learning difficulties in those with ADHD, as they suggest poorer reinforcement learning and lower behavioral persistence.

Consensus design of a calibration experiment for human fear conditioning.

Fear conditioning is a widely used laboratory model to investigate learning, memory, and psychopathology across species. The quantification of learning in this paradigm is heterogeneous in humans and psychometric properties of different quantification methods can be difficult to establish. To overcome this obstacle, calibration is a standard metrological procedure in which well-defined values of a latent variable are generated in an established experimental paradigm. These intended values then serve as validity criterion to rank methods. Here, we develop a calibration protocol for human fear conditioning. Based on a literature review, series of workshops, and survey of N = 96 experts, we propose a calibration experiment and settings for 25 design variables to calibrate the measurement of fear conditioning. Design variables were chosen to be as theory-free as possible and allow wide applicability in different experimental contexts. Besides establishing a specific calibration procedure, the general calibration process we outline may serve as a blueprint for calibration efforts in other subfields of behavioral neuroscience that need measurement refinement.

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.

Appraising reconsolidation theory and its empirical validation.

Re-exposure to elements of prior experiences can create opportunities for inducing amnesia for those events. The dominant theoretical framework posits that such re-exposure can result in memory destabilization, making the memory representation temporarily sensitive to disruption while it awaits reconsolidation. If true, such a mechanism that allows for memories to be permanently changed could have important implications for the treatment of several forms of psychopathology. However, there have been contradictory findings and elusive occurrences of replication failures within the "reconsolidation" field. Considering its potential relevance for clinical applications, the fact that this "hot" research area is being dominated by a single mechanistic theory, and the presence of unexplainable contradictory findings, we believe that it is both useful and timely to critically evaluate the reconsolidation framework. We discuss potential issues that may arise from how reconsolidation interference has typically been deducted from behavioral observations, and provide a principled assessment of reconsolidation theory that illustrates that the theory and its proposed boundary conditions are vaguely defined, which has made it close to impossible to refute reconsolidation theory. We advocate for caution, encouraging researchers not to blindly assume that a reconsolidation process must underlie their findings, and pointing out the risks of doing so. Finally, we suggest concrete theoretical and methodological advances that can promote a fruitful translation of reminder-dependent amnesia into clinical treatment.

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 effects of stress on avoidance in rodents: An unresolved matter.

In the face of a possible threat, a range of physiological (e.g., increased heart rate) and behavioral (e.g., avoidance or escape) responses are recruited. Here, we will focus on avoidance, in its persistent form one of the core symptoms of anxiety disorders and obsessive-compulsive disorder. The initial goal of fear and avoidance responses is to increase survival, but if they become persistent or overgeneralize, they can disrupt normal daily functioning, and ultimately even result in anxiety-related disorders. Relatedly, acute stress responses promote adaptation and survival, while chronic stress has been found to aggravate pathophysiology. Thus, stress might trigger the transition from adaptive to maladaptive responses, e.g., from goal-directed to persistent avoidance. Animal models are prime tools to unravel if and how stress influences avoidance. This is typically done by performing stress inductions prior to the assessment of (passive or active) avoidance behavior. Despite its clinical relevance, the current literature on this topic is fragmented, and an overall conclusion is lacking. In this Review, we first recapitulate the state of the art regarding stress and active as well as passive avoidance procedures. We then summarize the behavioral effects of acute and chronic stress on active and passive avoidance, and discuss the main neurobiological findings of the field. Finally, we highlight possible reasons for the largely contradictory findings in the literature and we propose strategies to further unravel the effect of stress on avoidance behavior. A deeper understanding of this currently unresolved matter may provide further insights in the etiology and treatment of anxiety-related disorders.

The continued need for animals to advance brain research.

Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised.

Overgeneralization of fear, but not avoidance, following acute stress.

Research has demonstrated the spreading of fear from threat-related stimuli to perceptually similar, but innocuous, stimuli. Less is known, however, about the generalization of avoidance behavior. Given that stress is known to affect learning and memory, we were interested in the effect of acute stress on (over)generalization of fear and avoidance responses. On the first day, one geometrical shape was paired with a mild electrical stimulus (CS+), whereas another shape was not (CS-). One day later, after participants had been exposed to the Maastricht Acute Stress Test or a control task, generalization of avoidance responses and fear (shock expectancy and skin conductance responses) was tested to a range of perceptual generalization stimuli. Generalization gradients were observed across different outcome measures. Stress enhanced generalization of shock expectancy to the stimulus most similar to the CS+. Our findings confirm that stress can affect the generalization of fear, but further studies are warranted.

Conditional Learning Deficits in Children with ADHD can be Reduced Through Reward Optimization and Response-Specific Reinforcement.

When children with ADHD are presented with behavioral choices, they struggle more than Typically Developing [TD] children to take into account contextual information necessary for making adaptive choices. The challenge presented by this type of behavioral decision making can be operationalized as a Conditional Discrimination Learning [CDL] task. We previously showed that CDL is impaired in children with ADHD. The present study explores whether this impairment can be remediated by increasing reward for correct responding or by reinforcing correct conditional choice behavior with situationally specific outcomes (Differential Outcomes). An arbitrary Delayed Matching-To-Sample [aDMTS] procedure was used, in which children had to learn to select the correct response given the sample stimulus presented (CDL). We compared children with ADHD (N = 45) and TD children (N = 49) on a baseline aDMTS task and sequentially adapted the aDMTS task so that correct choice behavior was rewarded with a more potent reinforcer (reward manipulation) or with sample-specific (and hence response-specific) reinforcers (Differential Outcomes manipulation). At baseline, children with ADHD performed significantly worse than TD children. Both manipulations (reward optimization and Differential Outcomes) improved performance in the ADHD group, resulting in a similar level of performance to the TD group. Increasing the reward value or the response-specificity of reinforcement enhances Conditional Discrimination Learning in children with ADHD. These behavioral techniques may be effective in promoting the learning of adaptive behavioral choices in children with ADHD.

Systematic Review: Attention-Deficit/Hyperactivity Disorder and Instrumental Learning.

OBJECTIVE: Although instrumental learning deficits are, among other deficits, assumed to contribute to attention-deficit/hyperactivity disorder (ADHD), no comprehensive systematic review of instrumental learning deficits in ADHD exists. This review examines differences between ADHD and typically developing (TD) children in basic instrumental learning and the effects of reinforcement form, magnitude, schedule, and complexity, as well as effects of medication, on instrumental learning in children with ADHD. METHOD: A systematic search of PubMed, PsyINFO, CINAHL, EMBASE+EMBASE CLASSIC, ERIC, and Web of Science was conducted for articles up to March 16, 2020. Experimental studies comparing instrumental learning between groups (ADHD versus TD) or a manipulation of reinforcement/medication within an ADHD sample were included. Quality of studies was assessed with an adapted version of the Hombrados and Waddington criteria to assess risk of bias in (quasi-) experimental studies. RESULTS: A total of 19 studies from among 3,384 non-duplicate screened articles were included. No difference in basic instrumental learning was found between children with ADHD and TD children, nor effects of form or magnitude of reinforcement. Results regarding reinforcement schedule and reversal learning were mixed, but children with ADHD seemed to show deficits in conditional discrimination learning compared to TD children. Methylphenidate improved instrumental learning in children with ADHD. Quality assessment showed poor quality of studies with respect to sample sizes and outcome and missing data reporting. CONCLUSION: The review identified very few and highly heterogenous studies, with inconsistent findings. No clear deficit was found in instrumental learning under laboratory conditions. Children with ADHD do show deficits in complex forms of learning, that is, conditional discrimination learning. Clearly more research is needed, using more similar task designs and manipulations.

Lack of drug-induced post-retrieval amnesia for auditory fear memories in rats.

BACKGROUND: Long-term memory formation is generally assumed to involve the permanent storage of recently acquired memories, making them relatively insensitive to disruption, a process referred to as memory consolidation. However, when retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example by pharmacologically interfering with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol). Here, we find that, contrary to expectations, systemic pharmacological manipulations in auditory fear-conditioned rats do not lead to drug-induced post-retrieval amnesia. RESULTS: In a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20-40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide), and consolidation of extinction memories (cycloheximide). CONCLUSIONS: In contrast with previously published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest.

Trait anxiety is associated with reduced typicality asymmetry in fear generalization.

In fear conditioning, training with typical category exemplars has been shown to promote fear generalization to novel exemplars of the same category, whereas training with atypical category exemplars supports limited if any generalization to other category members, amounting to a typicality asymmetry in fear generalization. The present study sought to examine how trait anxiety bears on typicality asymmetry in fear generalization. Participants in one condition were presented with typical exemplars during fear acquisition and atypical exemplars of the same category in the subsequent generalization test (typical condition), whereas in the other group, atypical and typical exemplars were presented during fear acquisition and generalization test, respectively (atypical condition). We observed a typicality asymmetry in fear generalization in self-reported expectancy ratings in low trait anxious individuals only. High trait anxious individuals showed a similar degree of fear generalization in both conditions. The current results help illuminate why some individuals are at risk for exhibiting broad fear generalization after exposure to an aversive event.

Reactivation-Dependent Amnesia for Contextual Fear Memories: Evidence for Publication Bias.

Research on memory reconsolidation has been booming in the last two decades, with numerous high-impact publications reporting promising amnestic interventions in rodents and humans. However, our own recently-published failed replication attempts of reactivation-dependent amnesia for fear memories in rats suggest that such amnestic effects are not always readily found and that they depend on subtle and possibly uncontrollable parameters. The discrepancy between our observations and published studies in rodents suggests that the literature in this field might be biased. The aim of the current study was to gauge the presence of publication bias in a well-delineated part of the reconsolidation literature. To this end, we performed a systematic review of the literature on reactivation-dependent amnesia for contextual fear memories in rodents, followed by a statistical assessment of publication bias in this sample. In addition, relevant researchers were contacted for unpublished results, which were included in the current analyses. The obtained results support the presence of publication bias, suggesting that the literature provides an overly optimistic overall estimate of the size and reproducibility of amnestic effects. Reactivation-dependent amnesia for contextual fear memories in rodents is thus less robust than what is projected by the literature. The moderate success of clinical studies may be in line with this conclusion, rather than reflecting translational issues. For the field to evolve, replication and non-biased publication of obtained results are essential. A set of tools that can create opportunities to increase transparency, reproducibility and credibility of research findings is provided.

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.

Perceptual variability: Implications for learning and generalization.

The generalization of learned behavior has been extensively investigated, but accounting for variance in generalized responding remains a challenge. Based on recent advances, we demonstrate that the inclusion of perceptual measures in generalization research may lead to a better understanding of both intra- and interindividual differences in generalization. We explore various ways through which perceptual variability can influence generalized responding. We investigate its impact on the ability to discriminate between stimuli and how similarity between stimuli may be variable, rather than fixed, because of it. Subsequently, we argue that perceptual variations can yield different learning experiences and that interindividual differences in generalized responding may be understood from this perspective. Finally, we point to the role of memory and decision-making within this context. Throughout this paper, we argue that accounting for perception in current generalization protocols will improve the precision of obtained generalization gradients and the ability to infer latent mechanisms. This can inspire future attempts to use generalization gradients as a (clinical) predictor or to relate them to individual traits and neural correlates and, ultimately, may lead to new theoretical and clinical insights.