A cognitive pathway to punishment insensitivity.

Individuals differ in their sensitivity to the adverse consequences of their actions, leading some to persist in maladaptive behaviors. Two pathways have been identified for this insensitivity: a motivational pathway based on excessive reward valuation and a behavioral pathway based on autonomous stimulus-response mechanisms. Here, we identify a third, cognitive pathway based on differences in punishment knowledge and use of that knowledge to suppress behavior. We show that distinct phenotypes of punishment sensitivity emerge from differences in what people learn about their actions. Exposed to identical punishment contingencies, some people (sensitive phenotype) form correct causal beliefs that they use to guide their behavior, successfully obtaining rewards and avoiding punishment, whereas others form incorrect but internally coherent causal beliefs that lead them to earn punishment they do not like. Incorrect causal beliefs were not inherently problematic because we show that many individuals benefit from information about why they are being punished, revaluing their actions and changing their behavior to avoid further punishment (unaware phenotype). However, one condition where incorrect causal beliefs were problematic was when punishment is infrequent. Under this condition, more individuals show punishment insensitivity and detrimental patterns of behavior that resist experience and information-driven updating, even when punishment is severe (compulsive phenotype). For these individuals, rare punishment acted as a "trap," inoculating maladaptive behavioral preferences against cognitive and behavioral updating.

Discovery and characterization of conserved binding of eIF4E 1 (CBE1), a eukaryotic translation initiation factor 4E-binding plant protein.

In many eukaryotes, translation initiation is regulated by proteins that bind to the mRNA cap-binding protein eukaryotic translation initiation factor 4E (eIF4E). These proteins commonly prevent association of eIF4E with eIF4G or form repressive messenger ribonucleoproteins that exclude the translation machinery. Such gene-regulatory mechanisms in plants, and even the presence of eIF4E-interacting proteins other than eIF4G (and the plant-specific isoform eIFiso4G, which binds eIFiso4E), are unknown. Here, we report the discovery of a plant-specific protein, conserved binding of eIF4E 1 (CBE1). We found that CBE1 has an evolutionarily conserved eIF4E-binding motif in its N-terminal domain and binds eIF4E or eIFiso4E in vitro CBE1 thereby forms cap-binding complexes and is an eIF4E-dependent constituent of these complexes in vivo Of note, plant mutants lacking CBE1 exhibited dysregulation of cell cycle-related transcripts and accumulated higher levels of mRNAs encoding proteins involved in mitosis than did WT plants. Our findings indicate that CBE1 is a plant protein that can form mRNA cap-binding complexes having the potential for regulating gene expression. Because mammalian translation factors are known regulators of cell cycle progression, we propose that CBE1 may represent such first translation factor-associated plant-specific cell cycle regulator.

The effect of encoding conditions on learning in the prototype distortion task.

The prototype distortion task demonstrates that it is possible to learn about a category of physically similar stimuli through mere observation. However, there have been few attempts to test whether different encoding conditions affect learning in this task. This study compared prototypicality gradients produced under incidental learning conditions in which participants performed a visual search task, with those produced under intentional learning conditions in which participants were required to memorize the stimuli. Experiment 1 showed that similar prototypicality gradients could be obtained for category endorsement and familiarity ratings, but also found (weaker) prototypicality gradients in the absence of exposure. In Experiments 2 and 3, memorization was found to strengthen prototypicality gradients in familiarity ratings in comparison to visual search, but there were no group differences in participants' ability to discriminate between novel and presented exemplars. Although the Search groups in Experiments 2 and 3 produced prototypicality gradients, they were no different in magnitude to those produced in the absence of stimulus exposure in Experiment 1, suggesting that incidental learning during visual search was not conducive to producing prototypicality gradients. This study suggests that learning in the prototype distortion task is not implicit in the sense of resulting automatically from exposure, is affected by the nature of encoding, and should be considered in light of potential learning-at-test effects.

The role of contingency awareness in single-cue human eyeblink conditioning.

Single-cue delay eyeblink conditioning is presented as a prototypical example of automatic, nonsymbolic learning that is carried out by subcortical circuits. However, it has been difficult to assess the role of cognition in single-cue conditioning because participants become aware of the simple stimulus contingency so quickly. In this experiment (n = 166), we masked the contingency to reduce awareness. We observed a strong relationship between contingency awareness and conditioned responding, with both trace and delay procedures. This finding suggests that explicit associative knowledge and anticipatory behavior are regulated by a coordinated system rather than by functionally and neurally distinct systems.

Unidirectional rating scales overestimate the illusory causation phenomenon.

Illusory causation is a phenomenon in which people mistakenly perceive a causal relationship between a cue and outcome even though the contingency between them is actually zero. Illusory causation studies typically use a unidirectional causal rating scale, where one endpoint refers to no relationship and the other to a strongly positive causal relationship. This procedure may bias mean causal ratings in a positive direction, either by censoring negative ratings or by discouraging participants from giving the normative rating of zero which is at the bottom extreme of the scale. To test this possibility, we ran two experiments that directly compared the magnitude of causal illusions when assessed with a unidirectional (zero-positive) versus a bidirectional (negative-zero-positive) rating scale. Experiment 1 used high cue and outcome densities (both 75%), whereas Experiment 2 used neutral cue and outcome densities (both 50%). Across both experiments, we observed a larger illusory causation effect in the unidirectional group compared with the bidirectional group, despite both groups experiencing the same training trials. The causal illusions in Experiment 2 were observed despite participants accurately learning the conditional probabilities of the outcome occurring in both the presence and absence of the cue, suggesting that the illusion is driven by the inability to accurately integrate conditional probabilities to infer causal relationships. Our results indicate that although illusory causation is a genuine phenomenon that is observable with either a undirectional or a bidirectional rating scale, its magnitude may be overestimated when unidirectional rating scales are used.

What makes a stimulus worthy of attention: Cue-outcome correlation and choice relevance in the learned predictiveness effect.

The learned predictiveness effect refers to the tendency for predictive cues to attract greater attention and show faster learning in subsequent tasks. However, in typical designs, the predictiveness of each cue (its objective cue-outcome correlation) is confounded with the degree to which it is informative for making the correct response on each trial (a feature we term choice relevance). In four experiments, we tested the unique contributions of cue-outcome correlation and choice relevance to the learned predictiveness effect by manipulating the outcome choices available on each trial. Experiments 1A and 1B compared two sets of partially predictive cues and found that participants learned more in a transfer phase about the set of cues that were previously choice-relevant. Experiments 2A and 2B used a design in which the cue-outcome correlation was stronger for one set of cues (perfect predictors) than the other set (imperfect predictors). Manipulating the choice relevance of the imperfect predictors in this design did not influence the magnitude of the learning bias toward the perfect predictor. Unlike cue-outcome correlation, choice relevance did not seem to correspond to biases in eye-gaze, suggesting that it operates via a distinct mechanism. Simulations with a modified EXIT model successfully predicted cue-outcome correlation and choice relevance effects by assuming that participants update learning for present outcomes only, but incorrectly predicted additive effects. We conclude that cue-outcome correlation and choice relevance are important factors that can lead to biases in future learning; both were individually sufficient but neither was necessary. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The role of uncertainty in regulating associative change.

Rescorla (2000, 2001) interpreted his compound test results to show that both common and individual error terms regulate associative change such that the element of a conditioned compound with the greater prediction error undergoes greater associative change than the one with the smaller prediction error. However, it has recently been suggested that uncertainty, not prediction error, is the primary determinant of associative change in people (Spicer et al., 2020, 2022). The current experiments use the compound test in a continuous outcome allergist task to assess the role of uncertainty in associative change, using two different manipulations of uncertainty: outcome uncertainty (where participants are uncertain of the level of the outcome on a particular trial) and causal uncertainty (where participants are uncertain of the contribution of the cue to the level of the outcome). We replicate Rescorla's compound test results in the case of both associative gains (Experiment 1) and associative losses (Experiment 3) and then provide evidence for greater change to more uncertain cues in the case of associative gains (Experiments 2 and 4), but not associative losses (Experiments 3 and 5). We discuss the findings in terms of the notion of theory protection advanced by Spicer et al., and other ways of thinking about the compound test procedure, such as that proposed by Holmes et al. (2019). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis.

Pathogenic ACAD9 variants cause complex I deficiency. Patients presenting in infancy unresponsive to riboflavin have high mortality. A six-month-old infant presented with riboflavin unresponsive lactic acidosis and life-threatening cardiomyopathy. Treatment with high dose bezafibrate and nicotinamide riboside resulted in marked clinical improvement including reduced lactate and NT-pro-brain type natriuretic peptide levels, with stabilized echocardiographic measures. After a long stable period, the child succumbed from cardiac failure with infection at 10.5 months. Therapy was well tolerated. Peak bezafibrate levels exceeded its EC50. The clinical improvement with this treatment illustrates its potential, but weak PPAR agonist activity of bezafibrate limited its efficacy.

Reduction in caffeine withdrawal after open-label decaffeinated coffee.

BACKGROUND: Withdrawal from addictive drugs can be reduced by administering placebo deceptively, but in the clinic it is unethical to deceive the patient. Open-label placebo effects have been observed across a range of psychophysiological phenomena, and may also apply to drug withdrawal. METHOD: 24-hour abstinent heavy coffee drinkers (N = 61) rated their caffeine withdrawal symptoms before being allocated to one of three groups. The Deceptive group was given decaffeinated coffee (decaf) and told it was caffeinated, the Open-Label group given decaf and told it was decaf and the Control group given water and told it was water. After 45 min, caffeine withdrawal was measured again. All participants rated their expectancies of withdrawal reduction from caffeinated coffee, decaf and water prior to being randomised and the end of the study. RESULTS: There was a significant 9.5-point reduction in caffeine withdrawal in the Open-Label group (95% confidence interval (CI): 4.7, 14.3; p = 0.002), which was 8.6 points less than the Deceptive group (95%CI: 0.4, 16.8; p = 0.014) but 8.9 points greater than the Control group (95%CI: 0.6, 17.2; p = 0.012). Pre-randomisation, participants expected caffeinated coffee to reduce their withdrawal symptoms the most, followed by water and decaf, Pre-randomisation expectancy of withdrawal was only associated with amount of withdrawal reduction in the Deceptive group. CONCLUSION: It appears as if open-label placebo caffeine (i.e. decaf) can reduce caffeine withdrawal symptoms, even when people do not hold a conscious expectancy it will do so. There may be ways to integrate open-label placebo procedures into clinical interventions for drug dependence without violating informed consent.

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).

Reduction of costly safety behaviors after extinction with a generalization stimulus is determined by individual differences in generalization rules.

Exposure-based treatment involves repeated presentation of feared stimuli or situations in the absence of perceived threat (i.e., extinction learning). However, the stimulus or situation of fear acquisition (CS+) is highly unlikely to be replicated and presented during treatment. Thereby, stimuli that resemble the CS+ (generalization stimuli; GSs) are typically presented. Preliminary evidence suggests that depending on how one generalizes fear (i.e., different generalization rules), presenting the same GS in extinction leads to differential effectiveness of extinction learning. The current study aimed to extend this finding to safety behaviors. After differential fear and avoidance conditioning, participants exhibited discrete generalization gradients that were consistent with their reported generalization rules (Similarity vs Linear). The Linear group showed stronger safety behaviors to a selected GS compared to the Similarity group, presumably due to higher threat expectancy. After extinction learning to this GS, the Linear group exhibited stronger reduction in safety behaviors generalization compared to the Similarity group. The results show that identifying distinct generalization rules allows one to predict expectancy violation to the extinction stimulus, in addition to corroborating the idea that strongly violating threat expectancy leads to better extinction learning and its generalization. With regard to clinical implications, identifying one's generalization rule (e.g., threat beliefs) help designing exposure sessions that evoke strong expectancy violation, enhancing the reduction in the generalization of maladaptive safety behaviors.

Inhibitory Learning with Bidirectional Outcomes: Prevention Learning or Causal Learning in the Opposite Direction?

Influential models of causal learning assume that learning about generative and preventive relationships are symmetrical to each other. That is, a preventive cue directly prevents an outcome from occurring (i.e., "direct" prevention) in the same way a generative cue directly causes an outcome to occur. However, previous studies from our lab have shown that many participants do not infer a direct prevention causal structure after feature-negative discrimination (A+/AB-) with a unidirectional outcome (Lee & Lovibond, 2021). Melchers et al. (2006) suggested that the use of a bidirectional outcome that can either increase or decrease from baseline, encourages direct prevention learning. Here we test an alternative possibility that a bidirectional outcome encourages encoding of a generative relationship in the opposite direction, where B directly causes a decrease in the outcome. Thus, previous evidence of direct prevention learning using bidirectional outcomes may instead be explained by some participants inferring an "Opposite Causal" structure. In two experiments, participants did indeed report an opposite causal structure. In Experiment 1, these participants showed the lowest outcome predictions when B was combined with a novel cause in a summation test, and lowest outcome predictions when B was presented alone. In Experiment 2, B successfully blocked learning to a novel cue that was directly paired with a reduction in the outcome, and this effect was strongest among participants who endorsed an Opposite Causal structure. We conclude that previous evidence of direct prevention learning using bidirectional outcomes may be a product of excitatory rather than inhibitory learning.

Retardation of acquisition after conditioned inhibition and latent inhibition training in human causal learning.

Inhibitory stimuli are slow to acquire excitatory properties when paired with the outcome in a retardation test. However, this pattern is also seen after simple nonreinforced exposure: latent inhibition. It is commonly assumed that retardation would be stronger for a conditioned inhibitor than for a latent inhibitor, but there is surprisingly little empirical evidence comparing the two in either animals or humans. Thus, retardation after inhibitory training could in principle be attributable entirely to latent inhibition. We directly compared the speed of excitatory acquisition after conditioned inhibition and matched latent inhibition training in human causal learning. Conditioned inhibition training produced stronger transfer in a summation test, but the two conditions did not differ substantially in a retardation test. We offer two explanations for this dissociation. One is that learned predictiveness attenuated the latent inhibition that otherwise would have occurred during conditioned inhibition training, so that retardation in that condition was primarily due to inhibition. The second explanation is that inhibitory learning in these experiments was hierarchical in nature, similar to negative occasion-setting. By this account, the conditioned inhibitor was able to negatively modulate the test excitor in a summation test, but was no more retarded than a latent inhibitor in its ability to form a direct association with the outcome. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Using unobserved causes to explain unexpected outcomes: The effect of existing causal knowledge on protection from extinction by a hidden cause.

People often rely on the covariation between events to infer causality. However, covariation between cues and outcomes may change over time. In the associative learning literature, extinction provides a model to study updating of causal beliefs when a previously established relationship no longer holds. Prediction error theories can explain both extinction and protection from extinction when an inhibitory (preventive) cue is present during extinction. In three experiments using the allergist causal learning task, we found that protection could also be achieved by a hidden cause that was inferred but not physically present, so long as that cause was a plausible preventer of the outcome. We additionally showed complete protection by a physically presented cue that was neutral rather than inhibitory at the outset of extinction. Both findings are difficult to reconcile with dominant prediction error theories. However, they are compatible with the idea of theory protection, where the learner attributes the absence of the outcome to the added cue (when present) or to a hidden cause, and therefore does not need to revise causal beliefs about A. Our results suggest that prediction error encourages changes in causal beliefs, but the nature of the change is determined by reasoning processes that incorporate existing knowledge of causal mechanisms and may be biased toward preservation of existing beliefs. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Inhibitory summation as a form of generalization.

Inhibitory learning after feature negative training (A+/AB-) is typically measured by combining the Feature B with a separately trained excitor (e.g., C) in a summation test. Reduced responding to C is taken as evidence that B has properties directly opposite to those of C. However, in human causal learning, transfer of B's inhibitory properties to another excitor is modest and depends on individual differences in inferred causal structure. Here we ask whether instead of opposing processes, a summation test might instead be thought of in terms of generalization. Using an allergist task, we tested whether inhibitory transfer would be influenced by similarity. We found that transfer was greater when the test stimuli were from the same semantic category as the training stimuli (Experiments 1 and 2) and when the test excitor had previously been associated with the same outcome (Experiment 3). We also found that the similarity effect applied across all self-reported causal structures. We conclude it may be more helpful to consider transfer of inhibition as a form of conceptual generalization rather than the arithmetic summation of opposing processes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Nonreactive testing: Evaluating the effect of withholding feedback in predictive learning.

Learning of cue-outcome relationships in associative learning experiments is often assessed by presenting cues without feedback about the outcome and informing participants to expect no outcomes to occur. The rationale is that this "no-feedback" testing procedure prevents new learning during testing that might contaminate the later test trials. We tested this assumption in 4 predictive learning experiments where participants were tasked with learning which foods (cues) were causing allergic reactions (the outcome) in a fictitious patient. We found that withholding feedback in a block of trials had no effect on causal ratings (Experiments 1 and 2), but it led to regression toward intermediate ratings when the missing feedback was embedded in the causal scenario and information about the outcome replaced by a "?" (Experiment 3). A factorial experiment manipulating cover story and feedback revealed that the regression-to-baseline effect was primarily driven by presentation of the "?" feedback (Experiment 4). We conclude that the procedure of testing without feedback, used widely in studies of human cognition, is an appropriate way of assessing learning, as long as the missing data are attributed to the experimenter and the absence of feedback is not highlighted in a way that induces uncertainty. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Reversal of inhibition by no-modulation training but not by extinction in human causal learning.

One of the many strengths of the Rescorla and Wagner (1972) model is that it accounts for both excitatory and inhibitory learning using a single error-correction mechanism. However, it makes the counterintuitive prediction that nonreinforced presentations of an inhibitory stimulus will lead to extinction of its inhibitory properties. Zimmer-Hart and Rescorla (1974) provided the first of several animal conditioning studies that contradicted this prediction. However, the human data are more mixed. Accordingly, we set out to test whether extinction of an inhibitor occurs in human causal learning after simultaneous feature negative training with a conventional unidirectional outcome. In 2 experiments with substantial sample sizes, we found no evidence of extinction after presentations of the inhibitory stimulus alone in either a summation test or causal ratings. By contrast, 2 "no-modulation" procedures that contradicted the original training contingencies successfully reversed inhibition. These results did not differ substantially as a function of participants' self-reported causal structures (configural/modulation/prevention). We hypothesize that inhibitory learning may be intrinsically modulatory, analogous to negative occasion-setting, even with simultaneous training. This hypothesis would explain why inhibition is reversed by manipulations that contradict modulation but not by simple extinction, as well as other properties of inhibitory learning such as imperfect transfer to another excitor. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Generalization following symmetrical intradimensional discrimination training.

A challenge for generalization models is to specify how excitation generated from a CS+ (i.e., positive evidence) should interact with inhibition from a CS- (i.e., negative evidence) to produce generalized responding. Empirically, many generalization phenomena are consistent with the monotonicity principle, which states that additional positive evidence should increase generalized responding, whereas additional negative evidence should decrease responding. However, a recent study (Lee et al.,, 2019) demonstrated that additional negative evidence can sometimes increase generalization, in direct contrast to animal data and associative accounts of generalization. The current study investigated whether a similar effect could be found in a symmetrical intradimensional discrimination procedure with two sources of negative evidence (CS-s) located on each side of a CS+. In three experiments, we compared generalization along a green-blue dimension between one group of participants who learned that an aqua-colored shape (CS+) predicted an outcome (Single Positive group) with another group who also learned that both a slightly greener and a slightly bluer shape led to no outcome (Double Negative group). Experiments 1A and 1B showed no effect of the additional negative evidence in increasing generalization around the CS+. However, changing a stimulus feature at test (shape) resulted in a higher gradient peak in the Double Negative group relative to the Single Positive group in Experiment 2. Although this result violates the monotonicity principle, an extended version of Blough's (1975) model applying cue competition to multiple stimulus dimensions (i.e., shape and color) successfully replicated the group differences. Our results suggest that associative mechanisms can account for some instances in which negative evidence increases generalization. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Second-Order Conditioning in Humans.

In contrast to the large body of work demonstrating second-order conditioning (SOC) in non-human animals, the evidence for SOC in humans is scant. In this review, I examine the existing literature and suggest theoretical and procedural explanations for why SOC has been so elusive in humans. In particular, I discuss potential interactions with conditioned inhibition, whether SOC is rational, and propose critical parameters needed to obtain the effect. I conclude that SOC is a real but difficult phenomenon to obtain in humans, and suggest directions for future research.

Inhibitory causal structures in serial and simultaneous feature negative learning.

We have previously reported that human participants trained with a simultaneous feature negative discrimination (intermixed A+/AB- trials) show only modest transfer of inhibitory properties of feature B to a separately trained excitor in a summation test. Their self-reported causal structure suggested that many participants learned that the effect of feature B was somewhat specific to the excitor it had been trained with (modulation), rather than learning that the feature prevented the outcome (prevention). This pattern is reminiscent of the distinction between negative occasion-setting and conditioned inhibition in the animal conditioning literature. However, in animals, occasion-setting is more commonly seen with a serial procedure, in which the feature (B) precedes the training excitor (A). Accordingly, we ran three experiments to compare serial with simultaneous training in an allergist causal judgement task. Transfer in a summation test was stronger to a previously modulated test excitor compared to a simple excitor after both simultaneous and serial training. There was a numerical trend towards a larger effect in the serial group, but it failed to reach significance and the Bayes Factor indicated support for the null. Serial training had no differential effect on the self-reported causal structure and did not significantly reduce overall transfer. After both simultaneous and serial training, transfer was strongest in participants who reported a prevention structure, replicating and extending our previous results to a previously modulated excitor. These results suggest that serial feature negative training does not promote a qualitatively different inhibitory causal structure compared to simultaneous training in humans.