No evidence that post-training dopamine D2 receptor agonism affects fear generalization in male rats.

BACKGROUND: The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. AIMS: The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) regarding fear generalization in adult, male Wistar rats, and aims to replicate previous findings in mice. METHODS: In a series of five experiments, D2R (ant)agonists were injected systemically, immediately after differential cued fear conditioning (CS+ followed by shock, CS- without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16, or 44 rats/group). In addition, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS- was assessed. RESULTS: We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting earlier research in mice, the evidence for the absence of an effect of D2R agonist quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test. CONCLUSION: In contrast with prior studies in mice, we have obtained evidence against a preventative effect of post-training D2R agonist quinpirole administration on subsequent fear generalization in rats.

Do we perceive sensations inside and outside of our body differently? Perceptual, emotional, and behavioral differences between visceral and somatic sensation, discomfort, and pain.

BACKGROUND: Experimental research evaluating differences between the visceral and somatic stimulation is limited to pain and typically uses different induction methods for visceral and somatic stimulation (e.g., rectal balloon distention vs. tactile hand stimulation). Our study aimed to compare differences in response time, intensity, unpleasantness, and threat between identical electrical visceral and somatic stimulations at both painful and non-painful perceptual thresholds. METHODS: Electrical stimulation was applied to the wrist and distal esophagus in 20 healthy participants. A double pseudorandom staircase determined perceptual thresholds of Sensation, Discomfort, and Pain for the somatic and visceral stimulations, separately. Stimulus reaction time (ms, via button press), and intensity, unpleasantness, and threat ratings were recorded after each stimulus. General linear mixed models compared differences in the four outcomes by stimulation type, threshold, and the stimulation type-by-threshold interaction. Sigmoidal maximum effect models evaluated differences in outcomes across all delivered stimulation intensities. KEY RESULTS: Overall, visceral stimulations were perceived as more intense, threatening, and unpleasant compared to somatic stimulations, but participants responded faster to somatic stimulations. There was no significant interaction effect, but planned contrasts demonstrated differences at individual thresholds. Across all delivered intensities, higher intensity stimulations were needed to reach the half-maximum effect of self-reported intensity, unpleasantness, and threat ratings in the visceral domain. CONCLUSIONS AND INFERENCES: Differences exist between modalities for both non-painful and painful sensations. These findings may have implications for translating paradigms and behavioral treatments from the somatic domain to the visceral domain, though future research in larger clinical samples is needed.

The effect of unpredictability on the perception of pain: a systematic review and meta-analysis.

ABSTRACT: Despite being widely assumed, the worsening impact of unpredictability on pain perception remains unclear because of conflicting empirical evidence, and a lack of systematic integration of past research findings. To fill this gap, we conducted a systematic review and meta-analysis focusing on the effect of unpredictability on pain perception. We also conducted meta-regression analyses to examine the moderating effect of several moderators associated with pain and unpredictability: stimulus duration, calibrated stimulus pain intensity, pain intensity expectation, controllability, anticipation delay, state and trait negative affectivity, sex/gender and age of the participants, type of unpredictability (intensity, onset, duration, location), and method of pain induction (thermal, electrical, mechanical pressure, mechanical distention). We included 73 experimental studies with adult volunteers manipulating the (un)predictability of painful stimuli and measuring perceived pain intensity and pain unpleasantness in predictable and unpredictable contexts. Because there are insufficient studies with patients, we focused on healthy volunteers. Our results did not reveal any effect of unpredictability on pain perception. However, several significant moderators were found, ie, targeted stimulus pain intensity, expected pain intensity, and state negative affectivity. Trait negative affectivity and uncontrollability showed no significant effect, presumably because of the low number of included studies. Thus, further investigation is necessary to clearly determine their role in unpredictable pain perception.

Expectations underlie the effects of unpredictable pain: a behavioral and electroencephalogram study.

ABSTRACT: Previous studies on the potential effects of unpredictability on pain perception and its neural correlates yielded divergent results. This study examined whether this may be explained by differences in acquired expectations. We presented 41 healthy volunteers with laser heat stimuli of different intensities. The stimuli were preceded either by predictable low, medium, or high cues or by unpredictable low-medium, medium-high, or low-high cues. We recorded self-reports of pain intensity and unpleasantness and laser-evoked potentials (LEPs). Furthermore, we investigated whether dynamic expectations that evolved throughout the experiment based on past trials were better predictors of pain ratings than fixed (nonevolving) expectations. Our results replicate previous findings that unpredictable pain is higher than predictable pain for low-intensity stimuli but lower for high-intensity stimuli. Moreover, we observed higher ratings for the medium-high unpredictable condition than the medium-low unpredictable condition, in line with an effect of expectation. We found significant interactions (N1, N2) for the LEP components between intensity and unpredictability. However, the few significant differences in LEP peak amplitudes between cue conditions did not survive correction for multiple testing. In line with predictive coding perspectives, pain ratings were best predicted by dynamic expectations. Surprisingly, expectations of reduced precision (increased variance) were associated with lower pain ratings. Our findings provide strong evidence that (dynamic) expectations contribute to the opposing effects of unpredictability on pain perception; therefore, we highlight the importance of controlling for them in pain unpredictability manipulations. We also suggest to conceptualize pain expectations more often as dynamic constructs incorporating previous experiences.

Examining the impact of cue similarity and fear learning on perceptual tuning.

Past research on the effects of associative aversive learning on discrimination acuity has shown mixed results, including increases, decreases, and no changes in discrimination ability. An animal study found that the type of learning experience determined the direction and extent of learning-induced changes. The current preregistered web-based study aimed to translate these findings to humans. Experiment 1 (N = 245) compared changes in stimulus discrimination between simple learning (only one oriented grating cue), coarse differential conditioning (physically distinct cues), and fine differential conditioning (physically similar cues) as well as to their three respective control groups. The discrimination task consisted of a two-alternative-forced-choice task with oriented grating stimuli. During learning, a specific orientation was paired with unpleasant pictures. Our analysis using generative modeling demonstrated weak to moderate evidence that aversive learning did not alter discrimination acuity in any of the groups. In a follow-up experiment (N = 121), we replicated these findings despite successful learning trajectories in all three groups and a more detailed assessment of discrimination acuity. Contrary to prior assumptions, our findings indicate that aversive learning does not enhance perceptual discrimination, and the presence of additional safety cues does not appear to moderate this effect.

The idiosyncratic nature of how individuals perceive, represent, and remember their surroundings and its impact on learning-based generalization.

The current study adopted a multimodal assessment approach to map the idiosyncratic nature of how individuals perceive, represent, and remember their surroundings and to investigate its impact on learning-based generalization. During an online differential conditioning paradigm, participants (n = 105) learned the pairing between a blue color patch (CS +) and an outcome (i.e., shock symbol) and the unpairing between a green color patch and the same outcome. After the learning task, the generalization of outcome expectancies was assessed to 14 stimuli spanning the entire blue-green color spectrum. Hereafter, a stimulus identification task assessed the ability to correctly identify the CS + among this stimulus range. Continuous and binary color category membership judgments of the stimuli were assessed preconditioning. We found that a response model with color perception and identification performance as sole predictors was preferred to contemporary approaches that use stimulus as a predictor. Interestingly, incorporating interindividual differences in color perception, CS identification, and color categories significantly improved the models' ability to account for different generalization patterns. Our findings suggest that insight into the idiosyncratic nature of how individuals perceive, represent, and remember their surroundings provides exciting opportunities to understand post-learning behaviors better. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Individual differences in stimulus identification, rule induction, and generalization of learning.

In the field of stimulus generalization, an old yet unresolved discussion pertains to what extent stimulus misidentifications contribute to the pattern of conditioned responding. In this article, we perform cluster analysis on six datasets (four published datasets and two unpublished datasets, included N = 950) to examine the relationship between interindividual differences in (a) stimulus identification, (b) patterns of generalized responding, and (c) verbalized generalization rules. The datasets were obtained from online predictive learning tasks where participants learned associations between colored cues and the presence or absence of a hypothetical outcome. In these datasets, stimulus identification and expectancy ratings were assessed in separate phases to a range of colors varying between blue-green. Using cluster analyses on performance during stimulus identification, we identified different subgroups of participants (good vs. bad identifiers). In all six datasets, we found a close relationship between the pattern of stimulus identification and the shape of the expectancy gradient across the test dimension between the identified subgroups. Furthermore, participants classified as good identifiers were more likely to report a similarity generalization rule than a relational or linear rule, suggesting that individual differences in stimulus identification are related to individual differences in generalization rules. These findings suggest that greater consideration should be given to interindividual variability in stimulus identification, inductive rules, and their relationship in explaining patterns of generalized responses. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Humans display interindividual differences in the latent mechanisms underlying fear generalization behaviour.

Human generalization research aims to understand the processes underlying the transfer of prior experiences to new contexts. Generalization research predominantly relies on descriptive statistics, assumes a single generalization mechanism, interprets generalization from mono-source data, and disregards individual differences. Unfortunately, such an approach fails to disentangle various mechanisms underlying generalization behaviour and can readily result in biased conclusions regarding generalization tendencies. Therefore, we combined a computational model with multi-source data to mechanistically investigate human generalization behaviour. By simultaneously modelling learning, perceptual and generalization data at the individual level, we revealed meaningful variations in how different mechanisms contribute to generalization behaviour. The current research suggests the need for revising the theoretical and analytic foundations in the field to shift the attention away from forecasting group-level generalization behaviour and toward understanding how such phenomena emerge at the individual level. This raises the question for future research whether a mechanism-specific differential diagnosis may be beneficial for generalization-related psychiatric disorders.

When experience is not enough: learning-based cognitive pain modulation with or without instructions.

ABSTRACT: The effects of expectations on pain perception are often studied using large differences in pain probabilities between experimental conditions, although they may be far more subtle in clinical contexts and, therefore, more difficult to detect. The current study aimed to investigate at which point subtle differences in pain probabilities can be detected and lead to differentiable expectations and perceptions. Furthermore, we investigated whether instructions can aid learning from experience and enhance subsequent pain modulatory effects. During a predictive learning task, participants were presented with 5 different cues, followed by either a high and low noxious stimulus. They learned about the different cue-stimulus contingencies either solely through experience (LEARN, N = 40) or a combination of experience and explicit information about the cue-stimulus contingencies (INSTRUCT, N = 40). We found that without explicit information, picking up the different pain probabilities was challenging, while explicit instruction significantly improved their detection. As revealed by drift diffusion modeling, learning from experience was insufficient for the development of a bias towards low pain even when it was highly likely. By contrast, when explicit information was provided, perception became more nuanced with the direction and extent of bias, capturing the subtle differences in pain probabilities. These findings highlight that the use of instructions to foster the detection of subtle pain improvements during pain treatment to enhance their cognitive pain modulatory effects warrant further investigation.

Cortico-Brainstem Mechanisms of Biased Perceptual Decision-Making in the Context of Pain.

Prior expectations can bias how we perceive pain. Using a drift diffusion model, we recently showed that this influence is primarily based on changes in perceptual decision-making (indexed as shift in starting point). Only during unexpected application of high-intensity noxious stimuli, altered information processing (indexed as increase in drift rate) explained the expectancy effect on pain processing. Here, we employed functional magnetic resonance imaging to investigate the neural basis of both these processes in healthy volunteers. On each trial, visual cues induced the expectation of high- or low-intensity noxious stimulation or signaled equal probability for both intensities. Participants categorized a subsequently applied electrical stimulus as either low- or high-intensity pain. A shift in starting point towards high pain correlated negatively with right dorsolateral prefrontal cortex activity during cue presentation underscoring its proposed role of "keeping pain out of mind". This anticipatory right dorsolateral prefrontal cortex signal increase was positively correlated with periaqueductal gray (PAG) activity when the expected high-intensity stimulation was applied. A drift rate increase during unexpected high-intensity pain was reflected in amygdala engagement and increased functional connectivity between amygdala and PAG. Our findings suggest involvement of the PAG in both decision-making bias and altered information processing to implement expectancy effects on pain. PERSPECTIVE: Modulation of pain through expectations has been linked to changes in perceptual decision-making and altered processing of afferent information. Our results suggest involvement of the dorsolateral prefrontal cortex, amygdala, and periaqueductal gray in these processes.

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.

Differences in perceptual memory determine generalization patterns.

Although memory of past experiences is crucial for the ability to transfer knowledge to new situations, surprisingly little research has directly investigated the relationship between memory and generalization. The present study sought to investigate how the perceptual memory of a trained stimulus influences generalization to similar stimuli. Forty participants underwent a fear conditioning procedure on Day 1, and separate memory recall and generalization tests on Day 2. We focused on two aspects of perceptual memory: namely memory bias (i.e., over- or underestimation of stimulus magnitude) and uncertainty. We found that memory bias predicted the pattern of generalized self-reported (expectancy ratings) and psychophysiological responses (fear-potentiated startle responses). Memory uncertainty was measured in two ways: self-reported uncertainty ratings and variability in stimulus recall. We found that higher levels of self-reported memory uncertainty corresponded with a broader generalization gradient on US expectancy, while greater variability in memory recall was associated with a broader generalization gradient on fear-potentiated startle responses. Taken together, our findings suggest that memory is an important determinant of generalized behavior and illustrate the need to account for these interindividual differences in perceptual memory when examining the generalization of learned responses.

The use of stimulus perception to account for variability in skin conductance responses to interoceptive stimuli.

Activity of the electrodermal response system is customarily expressed in relation to physical stimulus properties and not to perceived features. In situations where the delivery of physically identical stimuli can be challenging, such as in interoception research, this variability might pose a challenge for contemporary SCR analyses. Therefore, we investigated the extent to which activity in the electrodermal response system triggered by the delivery of interoceptive stimuli is better predicted by perceived intensity rather than physical input. For this purpose, we reanalyzed data from the baseline phase of a previous study (n = 60) in which skin conductance responses (SCRs) to innocuous esophageal stimulations of high and low intensities were recorded in addition to categorizations based on their perceived intensity (high or low). Using both peak scoring and model inversion methods, we found that the inclusion of stimulus perception as a predictor of the magnitude of the SCR increased model fit. These findings suggest that the inclusion of perception is a promising avenue to better model variability in psychophysiological responses to interoceptive stimuli.

Perceptual Decision Parameters and Their Relation to Self-Reported Pain: A Drift Diffusion Account.

Pain intensity ratings are subject to various cognitive modulations - yet the mechanisms underlying this influence are still not understood. In a conditioning protocol, pain-related expectations were induced through pairing predefined movements with a noxious or innocuous stimulus in either a predictable or unpredictable fashion. Healthy volunteers (N = 37) categorized the stimuli as either painful or nonpainful and rated its perceived intensity. Using a Hierarchical Drift Diffusion model based on the categorization data, we found that an a priori decision-making bias evolved toward the expected sensations (P < .001). In particular, our findings suggest that differences in both the amount of decision-making bias (P = .004) and the speed of sensory processing predict pain intensity ratings (P < .001). As such, changes in pain ratings could be based in either of these processes, which may require a different approach when targeted as part of psychological pain treatment. PERSPECTIVE: Changes in reported pain levels were linked to two distinct mechanisms, suggesting that increased pain reports could be attributed to either enhanced sensory processing or biased inferences. Our results might contribute to the development of person-tailored treatments based on the identification of latent mechanisms using computational models.

Direct and indirect effects of perception on generalization gradients.

For more than a century, researchers have attempted to understand why organisms behave similarly across situations. Despite the robust character of generalization, considerable variation in conditioned responding both between and within humans remains a challenge for contemporary generalization models. The current study aims to investigate the extent to which variation in behavior in a context of generalization can be attributed to differences in perception. We combined a fear conditioning and generalization procedure with a perceptual decision task in humans. We found that the failure to perceive a novel stimulus as different from the trained fear-evoking stimulus led to increased conditioned responding. Furthermore, perceptual errors yielded perceived stimulus-outcome contingencies that differed substantially from the objective contingencies. Final, the impact of a perceptual error was dependent upon these perceived contingencies. These findings suggest that generalization across a perceptual dimension is to a large extent driven by perceptual errors that directly affect behavior but also indirectly as they yield different learning experiences between individuals.

The Influence of Pain-Related Expectations on Intensity Perception of Nonpainful Somatosensory Stimuli.

OBJECTIVE: The extent to which pain-related expectations, known to affect pain perception, also affect perception of nonpainful sensations remains unclear, as well as the potential role of unpredictability in this context. METHODS: In a proprioceptive fear conditioning paradigm, various arm extension movements were associated with predictable and unpredictable electrocutaneous pain or its absence. During a subsequent test phase, nonpainful electrocutaneous stimuli with a high or low intensity were presented during movement execution. We used hierarchical drift diffusion modeling to examine the influence of expecting pain on the perceptual decision-making process underlying intensity perception of nonpainful sensations. In the first experiment (n = 36), the pain stimulus was never presented during the test phase after conditioning. In the second experiment (n = 39), partial reinforcement was adopted to prevent extinction of pain expectations. RESULTS: In both experiments, movements that were associated with (un)predictable pain led to higher pain expectancy, self-reported fear, unpleasantness, and arousal as compared with movements that were never paired with pain (effect sizes η2 ranging from 0.119 to 0.557; all p values < .05). Only in the second experiment-when the threat of pain remained present-we found that the expectation of pain affected decision making. Compared with the no pain condition, an a priori decision-making bias toward the high-intensity decision threshold was found with the strongest bias during unpredictable pain (effect sizes η2 ranging from 0.469 to 0.504; all p-values < .001). CONCLUSIONS: Thus, the expectation of pain affects inferential processes not only for subsequent painful but also for nonpainful bodily stimuli, with unpredictability moderating these effects, and only when the threat of pain remains present due to partial reinforcement.

Biased Intensity Judgements of Visceral Sensations After Learning to Fear Visceral Stimuli: A Drift Diffusion Approach.

A growing body of research has identified fear of visceral sensations as a potential mechanism in the development and maintenance of visceral pain disorders. However, the extent to which such learned fear affects visceroception remains unclear. To address this question, we used a differential fear conditioning paradigm with nonpainful esophageal balloon distensions of 2 different intensities as conditioning stimuli (CSs). The experiment comprised of preacquisition, acquisition, and postacquisition phases during which participants categorized the CSs with respect to their intensity. The CS+ was always followed by a painful electrical stimulus (unconditioned stimulus) during the acquisition phase and in 60% of the trials during postacquisition. The second stimulus (CS-) was never associated with pain. Analyses of galvanic skin and startle eyeblink responses as physiological markers of successful conditioning showed increased fear responses to the CS+ compared with the CS-, but only in the group with the low-intensity stimulus as CS+. Computational modeling of response times and response accuracies revealed that differential fear learning affected perceptual decision-making about the intensities of visceral sensations such that sensations were more likely to be categorized as more intense. These results suggest that associative learning might indeed contribute to visceral hypersensitivity in functional gastrointestinal disorders. PERSPECTIVE: This study shows that associative fear learning biases intensity judgements of visceral sensations toward perceiving such sensations as more intense. Learning-induced alterations in visceroception might therefore contribute to the development or maintenance of visceral pain.