Are depressive symptoms linked to a reduced pupillary response to novel positive information?-An eye tracking proof-of-concept study.

Introduction: Depressive symptoms have been linked to difficulties in revising established negative beliefs in response to novel positive information. Recent predictive processing accounts have suggested that this bias in belief updating may be related to a blunted processing of positive prediction errors at the neural level. In this proof-of-concept study, pupil dilation in response to unexpected positive emotional information was examined as a psychophysiological marker of an attenuated processing of positive prediction errors associated with depressive symptoms. Methods: Participants (N = 34) completed a modified version of the emotional Bias Against Disconfirmatory Evidence (BADE) task in which scenarios initially suggest negative interpretations that are later either confirmed or disconfirmed by additional information. Pupil dilation in response to the confirmatory and disconfirmatory information was recorded. Results: Behavioral results showed that depressive symptoms were related to difficulties in revising negative interpretations despite disconfirmatory positive information. The eye tracking results pointed to a reduced pupil response to unexpected positive information among people with elevated depressive symptoms. Discussion: Altogether, the present study demonstrates that the adapted emotional BADE task can be appropriate for examining psychophysiological aspects such as changes in pupil size along with behavioral responses. Furthermore, the results suggest that depression may be characterized by deviations in both behavioral (i.e., reduced updating of negative beliefs) and psychophysiological (i.e., decreased pupil dilation) responses to unexpected positive information. Future work should focus on a larger sample including clinically depressed patients to further explore these findings.

The effect of prediction error on overt attention and learning in humans.

It has been suggested that attention modulates the speed at which cues come to predict contingent outcomes, and that attention changes with the prediction errors generated by cues. Evidence for this interaction in humans is inconsistent, with divergent findings depending on whether attention was measured with eye fixations or learning speed. We included both measures in our experiment. Initially, predictive cues (A and B) were consistently followed by one outcome (o1), while nonpredictive cues (X and Y) were followed by two randomly alternating outcomes (o1 and o2). Consistent with an effect of prediction error, participants' fixated for longer on the nonpredictive cues than on the predictive ones. Then, the cues were combined in three pairs: AX, followed by o1, and AY and BX, followed by o2. Discrimination of AX and AY depended on the previously nonpredictive cues and, given that these received more attention during initial training, it should proceed faster than discrimination of AX and BX, which depended on the previously predictive cues. However, participants learned to predict the outcomes of AY and BX at a similar rate. The fixation times were similar for the previously predictive and previously nonpredictive cues. We discuss reasons that could explain these findings.

An attentional perspective on differential fear conditioning in chronic pain: The informational value of safety cues.

Differences in fear conditioning between individuals suffering from chronic pain and healthy controls may indicate a learning bias that contributes to the acquisition and persistence of chronic pain. However, evidence from lab-controlled conditioning studies is sparse and previous experiments have produced inconsistent findings. Twenty-five participants suffering from chronic back pain and twenty-five controls not reporting chronic pain took part in a differential fear conditioning experiment measuring attention (eye tracking) and autonomic arousal (pupil dilation and skin conductance) elicited by visual cues predicting the presence or absence of electric shock. In contrast to the healthy control group, participants with chronic pain did not acquire differential autonomic responding to cues of threat and safety and specifically failed to acquire any attentional preference for the safety cue over irrelevant contextual cues (while such preference was intact for the threat cue). We present simulations of a reinforcement learning model to show how the pattern of data can be explained by assuming that participants with chronic pain might have experienced less positive emotion (relief) when the electric shock was absent following safety cues. Our model shows how this assumption can explain both, reduced differential responding to cues of threat and safety as well as less selective attention to the safety cue.

Evidence for two attentional mechanisms during learning.

We sought to provide evidence for a combined effect of two attentional mechanisms during associative learning. Participants' eye movements were recorded as they predicted the outcomes following different pairs of cues. Across the trials of an initial stage, a relevant cue in each pair was consistently followed by one of two outcomes, while an irrelevant cue was equally followed by either of them. Thus, the relevant cue should have been associated with small relative prediction errors, compared to the irrelevant cue. In a later stage, each pair came to be followed by one outcome on a random half of the trials and by the other outcome on the remaining half, and thus there should have been a rise in the overall prediction error. Consistent with an attentional mechanism based on relative prediction error, an attentional advantage for the relevant cue was evident in the first stage. However, in accordance with a mechanism linked to overall prediction error, the attention paid to both types of cues increased at the beginning of the second stage. These results showed up in both dwell times and within-trial patterns of fixations, and they were predicted by a hybrid model of attention.

A rise in prediction error increases attention to irrelevant cues.

We investigated whether a sudden rise in prediction error widens an individual's focus of attention by increasing ocular fixations on cues that otherwise tend to be ignored. To this end, we used a discrimination learning task including cues that were either relevant or irrelevant for predicting the outcomes. Half of participants experienced contingency reversal once they had learned to predict the outcomes (reversal group, n = 30). The other half experienced the same contingencies throughout the task (control group, n = 30). As participants' prediction accuracy increased, they showed a decrease in the number of fixations directed to the irrelevant cues. Following contingency reversal, participants in the reversal group showed a drop in accuracy, indicating a rise in prediction error, and fixated on the irrelevant cues more often than participants in the control group. We discuss the results in the context of attentional theories of associative learning.

A test for a difference in the associability of blocked and uninformative cues in human predictive learning.

In human predictive learning, blocking, A+ AB+, and a simple discrimination, UX+ VX-, result in a stronger response to the blocked, B, than the uninformative cue, X (where letters represent cues and + and - represent different outcomes). To assess whether these different treatments result in more attention being paid to blocked than uninformative cues, Stage 1 in each of three experiments generated two blocked cues, B and E, and two uninformative cues, X and Y. In Stage 2, participants received two simple discriminations: either BX+ EX- and BY+ EY-, or BX+ BY- and EX+ EY-. If more attention is paid to blocked than uninformative cues, then the first pair of discriminations will be solved more readily than the second pair. In contrast to this prediction, both discriminations were acquired at the same rate. These results are explained by the theory of Mackintosh, by virtue of the assumption that learning is governed by an individual rather than a common error term.

Pupil dilation indicates the coding of past prediction errors: Evidence for attentional learning theory.

The attentional learning theory of Pearce and Hall () predicts more attention to uncertain cues that have caused a high prediction error in the past. We examined how the cue-elicited pupil dilation during associative learning was linked to such error-driven attentional processes. In three experiments, participants were trained to acquire associations between different cues and their appetitive (Experiment 1), motor (Experiment 2), or aversive (Experiment 3) outcomes. All experiments were designed to examine differences in the processing of continuously reinforced cues (consistently followed by the outcome) versus partially reinforced, uncertain cues (randomly followed by the outcome). We measured the pupil dilation elicited by the cues in anticipation of the outcome and analyzed how this conditioned pupil response changed over the course of learning. In all experiments, changes in pupil size complied with the same basic pattern: During early learning, consistently reinforced cues elicited greater pupil dilation than uncertain, randomly reinforced cues, but this effect gradually reversed to yield a greater pupil dilation for uncertain cues toward the end of learning. The pattern of data accords with the changes in prediction error and error-driven attention formalized by the Pearce-Hall theory.

Context modulation of learned attention deployment.

In three experiments, we investigated the contextual control of attention in human discrimination learning. In each experiment, participants initially received discrimination training in which the cues from Dimension A were relevant in Context 1 but irrelevant in Context 2, whereas the cues from Dimension B were irrelevant in Context 1 but relevant in Context 2. In Experiment 1, the same cues from each dimension were used in Contexts 1 and 2, whereas in Experiments 2 and 3, the cues from each dimension were changed across contexts. In each experiment, participants were subsequently shifted to a transfer discrimination involving novel cues from either dimension, to assess the contextual control of attention. In Experiment 1, measures of eye gaze during the transfer discrimination revealed that Dimension A received more attention than Dimension B in Context 1, whereas the reverse occurred in Context 2. Corresponding results indicating the contextual control of attention were found in Experiments 2 and 3, in which we used the speed of learning (associability) as an indirect marker of learned attentional changes. Implications of our results for current theories of learning and attention are discussed.

Fear acquisition and liking of out-group and in-group members: Learning bias or attention?

The present study explores the notion of an out-group fear learning bias that is characterized by facilitated fear acquisition toward harm-doing out-group members. Participants were conditioned with two in-group and two out-group faces as conditioned stimuli. During acquisition, one in-group and one out-group face was paired with an aversive shock whereas the other in-group and out-group face was presented without shock. Psychophysiological measures of fear conditioning (skin conductance and pupil size) and explicit and implicit liking exhibited increased differential responding to out-group faces compared to in-group faces. However, the results did not clearly indicate that harm-doing out-group members were more readily associated with fear than harm-doing in-group members. In contrast, the out-group face not paired with shock decreased conditioned fear and disliking at least to the same extent that the shock-associated out-group face increased these measures. Based on these results, we suggest an account of the out-group fear learning bias that relates to an attentional bias to process in-group information.

Reward Draws the Eye, Uncertainty Holds the Eye: Associative Learning Modulates Distractor Interference in Visual Search.

Stimuli in our sensory environment differ with respect to their physical salience but moreover may acquire motivational salience by association with reward. If we repeatedly observed that reward is available in the context of a particular cue but absent in the context of another cue the former typically attracts more attention than the latter. However, we also may encounter cues uncorrelated with reward. A cue with 50% reward contingency may induce an average reward expectancy but at the same time induces high reward uncertainty. In the current experiment we examined how both values, reward expectancy and uncertainty, affected overt attention. Two different colors were established as predictive cues for low reward and high reward respectively. A third color was followed by high reward on 50% of the trials and thus induced uncertainty. Colors then were introduced as distractors during search for a shape target, and we examined the relative potential of the color distractors to capture and hold the first fixation. We observed that capture frequency corresponded to reward expectancy while capture duration corresponded to uncertainty. The results may suggest that within trial reward expectancy is represented at an earlier time window than uncertainty.

Attentional Bias for Uncertain Cues of Shock in Human Fear Conditioning: Evidence for Attentional Learning Theory.

We conducted a human fear conditioning experiment in which three different color cues were followed by an aversive electric shock on 0, 50, and 100% of the trials, and thus induced low (L), partial (P), and high (H) shock expectancy, respectively. The cues differed with respect to the strength of their shock association (L < P < H) and the uncertainty of their prediction (L < P > H). During conditioning we measured pupil dilation and ocular fixations to index differences in the attentional processing of the cues. After conditioning, the shock-associated colors were introduced as irrelevant distracters during visual search for a shape target while shocks were no longer administered and we analyzed the cues' potential to capture and hold overt attention automatically. Our findings suggest that fear conditioning creates an automatic attention bias for the conditioned cues that depends on their correlation with the aversive outcome. This bias was exclusively linked to the strength of the cues' shock association for the early attentional processing of cues in the visual periphery, but additionally was influenced by the uncertainty of the shock prediction after participants fixated on the cues. These findings are in accord with attentional learning theories that formalize how associative learning shapes automatic attention.

Indicators of early and late processing reveal the importance of within-trial-time for theories of associative learning.

In four human learning experiments (Pavlovian skin conductance, causal learning, speeded classification task), we evaluated several associative learning theories that assume either an elemental (modified unique cue model and Harris' model) or a configural (Pearce's configural theory and an extension of it) form of stimulus processing. The experiments used two modified patterning problems (A/B/C+, AB/BC/AC+ vs. ABC-; A+, BC+ vs. ABC-). Pearce's configural theory successfully predicted all of our data reflecting early stimulus processing, while the predictions of the elemental theories were in accord with all of our data reflecting later stages of stimulus processing. Our results suggest that the form of stimulus representation depends on the amount of time available for stimulus processing. Our findings highlight the necessity to investigate stimulus processing during conditioning on a finer time scale than usually done in contemporary research.

The informational value of contexts affects context-dependent learning.

In two predictive-learning experiments, we investigated the role of the informational value of contexts for the formation of context-dependent behavior. During Phase 1 of each experiment, participants received either a conditional discrimination in which contexts were relevant (Group Relevant) or a simple discrimination in which contexts were irrelevant (Group Irrelevant). Each experiment also included an ABA renewal procedure. Participants received Z+ in context A during Phase 1, extinction of Z in context B during Phase 2, and were tested with Z in context A during a test phase. In each experiment, extinction of Z proceeded faster and was followed by stronger response recovery in Group Relevant than in Group Irrelevant. In Experiment 2, which included recording of eye-gaze behavior, dwell times on contexts were longer in Group Relevant than in Group Irrelevant. Our results support the idea that relevant contexts receive more attention, leading to stronger context specificity of learning.

Contextual control of attentional allocation in human discrimination learning.

In 3 human predictive learning experiments, we investigated whether the allocation of attention can come under the control of contextual stimuli. In each experiment, participants initially received a conditional discrimination for which one set of cues was trained as relevant in Context 1 and irrelevant in Context 2, and another set was relevant in Context 2 and irrelevant in Context 1. For Experiments 1 and 2, we observed that a second discrimination based on cues that had previously been trained as relevant in Context 1 during the conditional discrimination was acquired more rapidly in Context 1 than in Context 2. Experiment 3 revealed a similar outcome when new stimuli from the original dimensions were used in the test stage. Our results support the view that the associability of a stimulus can be controlled by the stimuli that accompany it.

An exploration of the feature-positive effect in adult humans.

Experiment 1 compared the acquisition of a feature-positive and a feature-negative discrimination in humans. In the former, an outcome was signaled by two stimuli together, but not by one of these stimuli alone. In the latter, the outcome was signaled by one stimulus alone, but not by two stimuli together. Using a within-group design, the experiment revealed that the feature-positive discrimination was acquired more readily than the feature-negative discrimination. Experiment 2 tested an explanation for these results, based on the Rescorla-Wagner theory, by examining how novel discriminations, based on a combination of a feature-positive and a feature-negative discrimination, were solved. The results did not accord with predictions from the theory. Alternative explanations for the results are considered.

Curved saccade trajectories reveal conflicting predictions in associative learning.

We report how the trajectories of saccadic eye movements are affected by memory interference acquired during associative learning. Human participants learned to perform saccadic choice responses based on the presentation of arbitrary central cues A, B, AC, BC, AX, BY, X, and Y that were trained to predict the appearance of a peripheral target stimulus at 1 of 3 possible locations, right (R), mid (M), or left (L), in the upper hemifield. We analyzed as measures of associative learning the frequency, latency, and curvature of saccades elicited by the cues and directed at the trained locations in anticipation of the targets. Participants were trained on two concurrent discrimination problems A+R, AC+R, AX+M, X+M and B+L, BC+L, BY+M, Y+M. From a connectionist perspective, cues were predicted to acquire associative links connecting the cues to the trained outcomes in memory. Model simulations based on the learning rule of the Rescorla and Wagner (1972) model revealed that for some cues, the prediction of the correct target location was challenged by the interfering prediction of an incorrect location. We observed that saccades directed at the correct location in anticipation of the target curved away from the location that was predicted by the interfering association. Furthermore, changes in curvature during training corresponded to predicted changes in associative memory. We propose that this curvature was caused by the inhibition of the incorrect prediction, as previously has been suggested with the concept of distractor inhibition (Sheliga, Riggio, & Rizzolatti, 1994; Tipper, Howard, & Houghton, 2000). The paradigm provides a new method to examine memory interference during associative learning.

Valproate-associated reversible encephalopathy in a 3-year-old girl with Pallister-Killian syndrome.

Valproic acid (VPA) is considered to be a drug of first choice for the therapy of generalized and focal epilepsies, including special epileptic syndromes. The drug is usually well tolerated, rare serious complications may occur in some patients, including hemorrhagic pancreatitis, coagulapathies, bone marrow suppression, VPA-induced hepatotoxicity and encephalopathy. We report a case of VPA-associated encephalopathy without hyperammonemia in a 3-year-old girl with Pallister-Killian-Syndrom, combined with a mild hepatopathy and thrombopathy. After withdrawal of VPA, the clinical symptoms and the electroencephalography-alterations vanished rapidly.

High incidence of vaproate-induced coagulation disorders in children receiving valproic acid: a prospective study.

Reports have been published on blood coagulation disturbances by valproate therapy. In the present prospective trial, blood samples were drawn before valproate therapy, after 6 weeks of therapy, after more than 6 weeks and after longer than 6 months of valproate therapy from 23 children newly treated with valproate. Two children developed thrombocytopenia, and six children with initial normal von Willebrand factor showed acquired von Willebrand's disease. Fibrinogen levels dropped below the lower limit in 12 patients and subnormal factor XIII plasma levels were observed in 17% of patients. No patient developed signs of hemorrhage. Eight percent of patients developed valproate-induced thrombocytopenia. Reduction in platelets did not reach statistic significance. Thrombelastography showed a 47% incidence of altered platelet function. We found a statistically significant, positive correlation between clotting time of collagen extrinsic pathway inhibitor and, accordingly, adenosindiphosphate and valproate level. Plasmatic coagulation investigations showed a significant decrease of prothrombin time. Activated partial thromboplastin time measurements also showed significant prolongation with valproate. Activity of von Willebrand factor antigen and von Willebrand factor ristocetin cofactor significantly decreased. Factor XIII activity significantly decreased after valproate therapy for longer than 6 months (17% of children). Fibrinogen was significantly reduced. In the coagulatory system a decrease in the main antiprotease antithrombin III activity was observed. Blood coagulation disturbances are common in patients with valproate, but rarely become clinically symptomatic. Acquired von Willebrand's disease and hypofibrinogenemia may become relevant in patients with surgery or trauma. Particular attention should be paid to factor-XIII deficiency, which is especially seen with valproate therapy.

Vagus nerve stimulation improves severely impaired heart rate variability in a patient with Lennox-Gastaut-Syndrome.

Vagus nerve stimulation (VNS) is a new therapeutic option for refractory epilepsy. We report a patient with Lennox-Gastaut-Syndrome (LGS) and a severe impairment of heart rate variability (HRV), we could demonstrate in our patient that HRV was improved by VNS.

Internet-based knowledge management database for children and adults with epilepsy: a possible model project for evidence-based medicine in the future.

With an incidence of nearly 1%, epilepsy represents one of the most frequent diseases in the population. Nevertheless substantial information gaps exist as to the exact incidence, prevalence, therapy and particularly to associated therapeutic success. Adequate studies are not performed on many of these issues which are primarily beyond the current interests of the pharmaceutical industry. An Internet-based knowledge management database is presented to illustrate initial results of the online system with a focus on medication and side effects (http://www.ligaepilepsie.org/KnowledgeDB/index.htm). Further, it is worth noting that this database was designed as a potential model for similar projects in other medical fields.