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Prediction errors (PEs) are generated when there are differences between an expected and an actual event or sensory input. The insula is a key brain region involved in pain processing, and studies have shown that the insula encodes the magnitude of an unexpected outcome (unsigned PEs). In addition to signaling this general magnitude information, PEs can give specific information on the direction of this deviation—i.e., whether an event is better or worse than expected. It is unclear whether the unsigned PE responses in the insula are selective for pain or reflective of a more general processing of aversive events irrespective of modality. It is also unknown whether the insula can process signed PEs at all. Understanding these specific mechanisms has implications for understanding how pain is processed in the brain in both health and in chronic pain conditions. In this study, 47 participants learned associations between 2 conditioned stimuli (CS) with 4 unconditioned stimuli (US; painful heat or loud sound, of one low and one high intensity each) while undergoing functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. We demonstrate that activation in the anterior insula correlated with unsigned intensity PEs, irrespective of modality, indicating an unspecific aversive surprise signal. Conversely, signed intensity PE signals were modality specific, with signed PEs following pain but not sound located in the dorsal posterior insula, an area implicated in pain intensity processing. Previous studies have identified abnormal insula function and abnormal learning as potential causes of pain chronification. Our findings link these results and suggest that a misrepresentation of learning relevant PEs in the insular cortex may serve as an underlying factor in chronic pain. This study uses a learning paradigm including pain and sound stimuli to show that the human posterior insula encodes signed intensity prediction errors for pain but not sound, whereas unsigned intensity and modality prediction errors are encoded in the anterior insula for both stimulus modalities. [ABSTRACT FROM AUTHOR]

While the examination of conditioned cardiac responses is well established in human fear conditioning research, comparable studies using less‐aversive or rather appetitive unconditioned stimuli (UCS) are sparse and results are mixed. Therefore, the aim of this study was a systematic analysis of cardiac reactions in aversive and appetitive conditioning. Olfactory stimuli were used as unconditioned stimuli as they are suitable reinforcers in both an aversive and an appetitive conditioning offering the opportunity for a comparison between conditioned responses. In total, n = 86 participants took part in both an aversive and an appetitive differential conditioning task with a counterbalanced order across participants. Aversive or appetitive odors, respectively, served as UCS and neutral geometrical figures as CS. Subjective ratings, skin conductance response (SCRs), and evoked cardiac reactions were analyzed and compared between tasks. Conditioned responses in subjective ratings could be observed in both aversive conditioning and appetitive conditioning, while SCRs discriminated between CS+ and CS− in aversive conditioning only. Regarding conditioned cardiac responses, the deceleration for the CS+ was longer than for the CS− in both tasks. In addition, a higher deceleration magnitude and a shorter acceleration for the CS+ as compared to the CS− were found in aversive but not in appetitive conditioning. There were medium‐size correlations between aversive and appetitive CRs for subjective ratings and none for physiological responses. The results suggest similarities between cardiac response patterns in aversive and appetitive conditioning, which implies that bradycardia in conditioning might not be fear‐specific but presents a valence‐independent CS‐elicited bradycardia. Cardiac slowing in response to fear conditioned stimuli is a well‐known phenomenon (i.e., "fear bradycardia"). Here, conditioned stimuli in aversive and appetitive olfactory conditioning evoked slowing of heart rate, suggesting that conditioned bradycardia may be less specific to fear than previously thought. [ABSTRACT FROM AUTHOR]

• At least 10 different measures of human threat conditioning exist in the literature. • Measures are highly variable in translational, cognitive and methodological aspects. • Evidence of the measures reflecting amygdala-dependent learning in humans is scarce. • Formal learning models have mostly been studied for skin conductance responses. • Startle eye-blink and pupil size seem to best discriminate CS+/CS−. Threat conditioning is a laboratory model of associative learning across species that is often used in research on the etiology and treatment of anxiety disorders. At least 10 different conditioned responses (CR) for quantifying learning in human threat conditioning are found in the literature. In this narrative review, we discuss these CR by considering the following questions: (1) Are the CR indicators of amygdala-dependent threat learning? (2) To what components of formal learning models do the CR relate? (3) How well can threat learning be inferred from the CR? Despite a vast literature, these questions can only be answered for some CR. Among the CR considered, heart period, startle eye-blink and Pavlovian-to-instrumental transfer are most clearly related to amygdala-dependent threat learning. Formal learning models have mostly been studied for skin conductance responses, which are likely to reflect threat prediction and its uncertainty. Startle eye-blink and pupil size appear to best differentiate CS+/CS−, although few direct comparisons between CR exist. We suggest future directions for improving the quantification of threat conditioning. [ABSTRACT FROM AUTHOR]

Background: Extinction-based procedures are often used to inhibit maladaptive fear responses. However, because extinction procedures show efficacy limitations, transcranial direct current stimulation (tDCS) has been suggested as a promising add-on enhancer. Objective: In this study, we tested how cathodal tDCS over the right dorsolateral prefrontal cortex affects extinction and tried to unveil the processes at play that boost the effectiveness of extinction procedures and its translational potential to the treatment of anxiety disorders. Methods: We implemented a fear conditioning paradigm whereby 41 healthy women (mean age = 20.51 ± 5.0) were assigned to either cathodal tDCS (n = 27) or sham tDCS (n = 16). Fear responses were measured with self-reports, autonomic responses, and implicit avoidance tendencies. Results: Cathodal tDCS shows no statistically significant effect in extinction, according to self-reports, and seems to even negatively affect fear conditioned skin conductance responses. However, one to three months after the tDCS session and extinction, we found a group difference in the action tendencies towards the neutral stimuli (F (1, 41) = 12.04, p = .001, ηp2 = .227), with the cathodal tDCS group (as opposed to the sham group) showing a safety learning (a positive bias towards the CS-), with a moderate effect size. This suggests that cathodal tDCS may foster stimuli discrimination, leading to a decreased generalization effect. Discussion: Cathodal tDCS may have enhanced long-term distinctiveness between threatening cues and perceptively similar neutral cues through a disambiguation process of the value of the neutral stimuli—a therapeutic target in anxiety disorders. Future studies should confirm these results and extend the study of cathodal tDCS effect on short term avoidance tendencies. [ABSTRACT FROM AUTHOR]

Learning to predict threat from environmental cues is a fundamental skill in changing environments. This aversive learning process is exemplified by Pavlovian threat conditioning. Despite a plethora of studies on the neural mechanisms supporting the formation of associations between neutral and aversive events, our computational understanding of this process is fragmented. Importantly, different computational models give rise to different and partly opposing predictions for the trial-by-trial dynamics of learning, for example expressed in the activity of the autonomic nervous system (ANS). Here, we investigate human ANS responses to conditioned stimuli during Pavlovian fear conditioning. To obtain precise, trial-by-trial, single-subject estimates of ANS responses, we build on a statistical framework for psychophysiological modelling. We then consider previously proposed non-probabilistic models, a simple probabilistic model, and non-learning models, as well as different observation functions to link learning models with ANS activity. Across three experiments, and both for skin conductance (SCR) and pupil size responses (PSR), a probabilistic learning model best explains ANS responses. Notably, SCR and PSR reflect different quantities of the same model: SCR track a mixture of expected outcome and uncertainty, while PSR track expected outcome alone. In summary, by combining psychophysiological modelling with computational learning theory, we provide systematic evidence that the formation and maintenance of Pavlovian threat predictions in humans may rely on probabilistic inference and includes estimation of uncertainty. This could inform theories of neural implementation of aversive learning. [ABSTRACT FROM AUTHOR]

Attending to stimuli that share perceptual similarity to learned threats is an adaptive strategy. However, prolonged threat generalization to cues signalling safety is considered a core feature of pathological anxiety. One potential factor that may sustain over-generalization is sensitivity to future threat uncertainty. To assess the extent to which Intolerance of Uncertainty (IU) predicts threat generalization, we recorded skin conductance in 54 healthy participants during an associative learning paradigm, where threat and safety cues varied in perceptual similarity. Lower IU was associated with stronger discrimination between threat and safety cues during acquisition and extinction. Higher IU, however, was associated with generalized responding to threat and safety cues during acquisition, and delayed discrimination between threat and safety cues during extinction. These results were specific to IU, over and above other measures of anxious disposition. These findings highlight: (1) a critical role of uncertainty-based mechanisms in threat generalization, and (2) IU as a potential risk factor for anxiety disorder development. [ABSTRACT FROM AUTHOR]

Generalization of conditioned fear has been implicated in the maintenance and proliferation of fear in anxiety disorders. The role of cognitive processes in generalization of conditioning is an important yet understudied issue. Vervliet et al. (2010) tested generalization of fear to a visual stimulus of a particular color and shape paired with electric shock. Test stimuli shared either the color or shape of the CS+. Prior to conditioning, participants were instructed that either color or shape would be predictive of shock. Generalization was stronger to the stimulus containing the instructed feature, suggesting that instructions impacted generalization of fear. However, the result may also reflect the impact of instructions on attention and learning during the conditioning phase. In the present study, the instructional manipulation was given after the conditioning phase to control for any impact of instructions on learning. A similar result to that reported by Vervliet et al. was observed. On self-reported expectancy of shock, generalization was greater to the test stimulus that included the instructed stimulus feature. The same pattern was observed on skin conductance, although it did not reach statistical significance. The findings indicate that explicitly instructed information affected generalization of conditioned fear independently of any impact on learning, pointing to the role of cognitive processes in human fear generalization. They also support the utility of cognitive therapy approaches, which are employed after fear has already developed, in addressing clinical overgeneralization. [ABSTRACT FROM AUTHOR]

Following differential fear conditioning, the instruction that the unconditional stimulus will no longer be presented (instructed extinction) reduces differential electrodermal responding to CS+ and CS−, but does not affect differential conditional stimulus valence evaluations. Reductions in differential electrodermal responding have been attributed to the provision of verbal instructions; however, during instructed extinction the unconditional stimulus electrode is often removed as well. This removal could reduce the participants' general arousal levels rendering the detection of differential electrodermal responding difficult. The current study examined this alternative interpretation by comparing the electrodermal responses and conditional stimulus valence evaluations of an instruction/electrode-on group, an instruction/electrode-off group, and a control group who were not instructed. Following instructed extinction, differential electrodermal responding was eliminated in both instruction groups, an effect that was not influenced by the attachment/removal of the electrode. Replicating previous findings, conditional stimulus valence was not affected by instructed extinction. The results suggest that verbal instructions, not unconditional stimulus electrode removal, reduce differential electrodermal responding during instructed extinction manipulations. [ABSTRACT FROM AUTHOR]

Abstract: Disruption of the reconsolidation of conditioned fear memories has been suggested as a non-pharmacological means of preventing the return of learned fear in human populations. A reconsolidation update paradigm was developed in which a reconsolidation window is opened by a single isolated retrieval trial of a previously reinforced CS+ which is then followed by Extinction Training within that window. However, follow-up studies in humans using multi-methods fear conditioning indices (e.g., fear-potentiated startle, skin conductance, US-expectancy) have failed to replicate the retrieval+extinction effects. In the present study, we further investigated the retrieval+extinction reconsolidation update paradigm by directly comparing the acquisition, extinction, and return of fear-potentiated startle in the absence or presence of US-expectancy measures (using a trial-by-trial response keypad) with and without retrieval of a previously acquired CS-US association. Participants were fear conditioned to two visual cue CS+’s, one of which was presented as a single, isolated retrieval trial before Extinction Training and one that was extinguished as usual. The results show that the inclusion of US-expectancy measures strengthens the CS–US association to provide enhanced fear conditioning and maintenance of fear memories over the experimental sessions. In addition, in the groups that used on-line US-expectancy measures, the retrieval+extinction procedure reduced reinstatement of fear-potentiated startle to both previously reinforced CS+’s, as compared to the extinction as usual group. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Background: Women are twice as likely as men to develop Posttraumatic Stress Disorder (PTSD). Abnormal acquisition of conditioned fear has been suggested as a mechanism for the development of PTSD. While some studies of healthy humans suggest that women are either no different or express less conditioned fear responses during conditioning relative to men, differences in the acquisition of conditioned fear between men and women diagnosed with PTSD has not been examined. Methods: Thirty-one participants (18 men; 13 women) with full or subsyndromal PTSD completed a fear conditioning task. Participants were shown computer-generated colored circles that were paired (CS+) or unpaired (CS−) with an aversive electrical stimulus and skin conductance levels were assessed throughout the task. Results: Repeated measures ANOVA indicated a significant sex by stimulus interaction during acquisition. Women had greater differential conditioned skin conductance responses (CS + trials compared to CS− trials) than did men, suggesting greater acquisition of conditioned fear in women with PTSD. Conclusions: In contrast to studies of healthy individuals, we found enhanced acquisition of conditioned fear in women with PTSD. Greater fear conditioning in women may either be a pre-existing vulnerability trait or an acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD. Characterizing the underlying mechanisms of these differences is needed to clarify sex-related differences in the pathophysiology of PTSD. [Copyright &y& Elsevier]

Abstract: In two conditioning experiments with humans, we found that participants’ prior experience exerted considerable influence on later learning of configural discrimination problems. Prior experience was manipulated by pre-training participants before the main acquisition stage. They either received a discrimination problem that encouraged an elemental solution (A+, B−, AB+, CD− in Experiment 1 and A+, AB+, C−, CB− in Experiment 2) or one that required a configural solution (AB+, BC−, CD+, DA− in Experiment 1 and A−, AB+, C+, CB− in Experiment 2). Then, all participants were shown a discrimination that required a configural solution (E+, F+, EF− in Experiment 1 and DE+, EF−, FG+, GD− in Experiment 2). In both experiments, participants who had received elemental pre-training were impaired on the later configural problem compared to participants who had received configural pre-training. The results suggest that organisms can flexibly process stimuli elementally or configurally. [Copyright &y& Elsevier]

We examined the possibility of nonconscious associative learning in a context of skin conductance conditioning, using emotional facial expressions as stimuli. In the first experiment, subjects were conditioned to a backwardly masked angry face that was followed by electric shock, with a masked happy face as the nonreinforced stimulus. In spite of the effectively masked conditioned stimuli, differential conditioned skin conductance responses were observed in a subsequent nonmasked extinction phase. This effect could not be attributed to differential sensitization or pseudo-conditioning. In the second experiment, the differential responding during extinction was replicated with angry but not with happy faces as conditioned stimuli. It was concluded that with fear-relevant facial expressions as the conditioned stimulus, associative learning was possible even in conditions where the subjects remained unaware of the conditioned stimulus and its relationship to the unconditioned stimulus. [ABSTRACT FROM AUTHOR]

Threat responses are often shaped by social information, such as observation of aversive outcomes for others. Yet, the neurochemistry regulating observational learning of threats is largely unknown. Here, we examined the impact of the GABAergic and noradrenergic system, which are central in regulating threat learning from first-hand experiences, on observational threat learning in humans. To this end, 61 participants received either 1 mg Lorazepam (enhancing GABAergic signalling N = 18), 20 mg Yohimbine (enhancing Noradrenergic transmission, N = 16), Placebo (double blind and randomized control for Lorazepam and Yohimbine, N = 12) or no treatment (N = 15) prior to observational threat conditioning. Participants acquired conditioned threat responses by observation of another individual who is presented with a conditioned stimulus (CS) and an aversive unconditioned stimulus (US). Participants' threat responses were tested by direct exposure to the CSs immediately after learning, as well as two days later (drug free). Our results indicate decreased fear ratings to socially acquired CSs by enhanced GABAergic transmission as compared to the control group (placebo and no treatment) during the immediate test. We could not provide evidence for noradrenergic modulation of socially acquired threat responses. Further, we found no differences in psychophysiological responses (Skin conductance responses) or long-term persistence of conditioned responses. Our results provide initial evidence for an impact of the GABAergic system on social acquisition of threats. • Observational threat learning results in expression of conditioned responses (SCR, fear ratings, US expectancy) up to two days after learning • Enhanced GABAergic transmission reduces expression of conditioned responses (learned by observation) immediately after learning • Enhanced noradrenergic transmission has no effect on conditioned responses that are shaped by observational learning [ABSTRACT FROM AUTHOR]