Better, worse, or different than expected: on the role of value and identity prediction errors in fear memory reactivation.

Although reconsolidation-based interventions constitute a promising new avenue to treating fear and anxieties disorders, the success of the intervention is not guaranteed. The initiation of memory reconsolidation is dependent on whether a mismatch between the experienced and predicted outcome-a prediction error (PE)-occurs during fear memory reactivation. It remains, however, elusive whether any type of PE renders fear memories susceptible to reconsolidation disruption. Here, we investigated whether a value PE, elicited by an outcome that is better or worse than expected, is necessary to make fear memories susceptible to reconsolidation disruption or whether a model-based identity PE, i.e., a PE elicited by an outcome equally aversive but different than expected, would be sufficient. Blocking beta-adrenergic receptors with propranolol HCl after reactivation did, however, not reduce the expression of fear after either type of PE. Instead, we observed intact fear memory expression 24 h after reactivation in the value-, identity- and a no-PE control group. The present results do not corroborate our earlier findings of reconsolidation disruption and point towards challenges that the field is currently facing in observing evidence for memory reconsolidation at all. We provide potential explanations for the unexpected failure of replicating reconsolidation disruption and discuss future directions.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques.

TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active in vitro against a panel of 29 Francisella tularensis isolates, showing MICs against 50% and 90% of isolates of 0.25 and 0.5 µg/ml, respectively. In a mouse model of inhalational tularemia, animals were exposed by aerosol to 91 to 283 50% lethal doses (LD50)/mouse of F. tularensis SCHU S4. Following 21 days of once-daily intraperitoneal dosing with TP-271 at 3, 6, 12, and 18 mg/kg of body weight/day, initiating at 24 h postchallenge, survival was 80%, 100%, 100%, and 100%, respectively. When treatment was initiated at 72 h postchallenge, survival was 89%, 100%, 100%, and 100% in the 3-, 6-, 12-, and 18-mg/kg/day TP-271 groups, respectively. No mice treated with the vehicle control survived. Surviving mice treated with TP-271 showed little to no relapse during 14 days posttreatment. In a nonhuman primate model of inhalational tularemia, cynomolgus macaques received an average aerosol exposure of 1,144 CFU of F. tularensis SCHU S4. Once-daily intravenous infusion with 1 or 3 mg/kg TP-271, or vehicle control, for 21 days was initiated within 6 h of confirmed fever. All animals treated with TP-271 survived to the end of the study, with no relapse during 14 days after the last treatment, whereas no vehicle control-treated animals survived. The protection and low relapse afforded by TP-271 treatment in these studies support continued investigation of TP-271 for use in the event of aerosolized exposure to F. tularensis.

Fear conditioning, persistence of disruptive behavior and psychopathic traits: an fMRI study.

Children diagnosed with Disruptive Behavior Disorders (DBD), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Deficient fear conditioning may be a key mechanism underlying persistence, and has been associated with altered regional brain function in adult antisocial populations. In this study, we investigated the associations between the neural correlates of fear conditioning, persistence of childhood-onset DBD during adolescence and psychopathic traits. From a cohort of children arrested before the age of 12 years, participants who were diagnosed with Oppositional Defiant Disorder or Conduct Disorder in previous waves (mean age of onset 6.5 years, s.d. 3.2) were reassessed at mean age 17.6 years (s.d. 1.4) and categorized as persistent (n=25) or desistent (n=25) DBD. Using the Youth Psychopathic Traits Inventory and functional magnetic resonance imaging during a fear conditioning task, these subgroups were compared with 26 matched healthy controls from the same cohort. Both persistent and desistent DBD subgroups were found to show higher activation in fear processing-related brain areas during fear conditioning compared with healthy controls. In addition, regression analyses revealed that impulsive-irresponsible and grandiose-manipulative psychopathic traits were associated with higher activation, whereas callous-unemotional psychopathic traits were related to lower activation in fear-related areas. Finally, the association between neural activation and DBD subgroup membership was mediated by impulsive-irresponsible psychopathic traits. These results provide evidence for heterogeneity in the neurobiological mechanisms underlying psychopathic traits and antisocial behavior and, as such, underscore the need to develop personalized interventions.

The urge to smoke depends on the expectation of smoking.

AIMS: An earlier study (Dols et al. 2000) suggested that cue-induced urge to smoke depends on the expectation of smoking. The present study tried to replicate the findings under stringently controlled conditions. DESIGN: A 2 (context) x 2 (cues) x 6 (trial) within-subject design. Each smoker entered two different contexts; one context predicted the future occurrence of smoking (i.e. one puff of a cigarette) and one context predicted the non-occurrence of smoking. In each context smokers were exposed to smoking cues (i.e. cigarettes and lighter) or not. SETTING: Laboratory at Maastricht University. PARTICIPANTS: Thirty-two daily smokers, smoking at least five cigarettes a day for at least 2 years. MEASUREMENTS: Participants reported their urge to smoke in each context in the presence and absence of smoking cues using a computerized visual analogue scale (VAS). FINDINGS: The results revealed that the urge to smoke was higher in a context in which smoking was expected relative to a context in which it was not expected. As in the previous study the urge-inducing effect of smoking cues was larger in the smoking context than in the non-smoking context. Moreover, smoking cues did not have a significant effect in the non-smoking context. CONCLUSIONS: It was shown that smoking cues elicit craving due mainly to a generated expectation of the occurrence of smoking and less due to salience or long history of associative learning. Theoretical and practical implications of the results are discussed.

Autobiographical memories become less vivid and emotional after eye movements.

OBJECTIVES: To test (1) whether eye movements during retrieval of emotional memories are followed by less vividness and less emotionality of future recollections, (2) whether this effect, if present, is stronger than the effects of a control activity (finger tapping), (3) whether the alleged effects of tapping and eye movements are stronger than a no-movement, control condition (mere imagery), (4) whether reductions in vividness and emotionality after eye movements (and finger tapping) are specific to negative memories or also occur in the case of positive memories. METHOD: Sixty healthy volunteers recalled either positive or negative memories and scored the vividness and emotionality of the recollections. Next, memories were recalled whilst the participant was performing rapid eye movements, finger tapping, or not performing a dual task. Then participants were asked to recall the event again and to rate its vividness and emotionality. RESULTS: Compared to finger tapping and the no-dual-task condition, recollections after eye movements made future recollections less vivid. After eye movements, but not after the other interventions, negative memories became less negative, and positive memories became less positive. CONCLUSION: The findings show that eye movements not only reduce vividness and emotionality of memories during the eye moving, but also affect future recollections, during which no eye movements are made. Some theoretical explanations are discussed. As to clinical implications, it is suggested that if there is a role for eye-movement-based treatments, it is very limited.

A reaction time paradigm to assess (implicit) complaint-specific dysfunctional beliefs.

We investigated whether an implicit association test (IAT) can be used to assess dysfunctional beliefs in the realm of psychopathology. As a first exploration we therefore constructed a IAT that was designed to differentiate between high and low social anxious individuals. Social situation and neutral words were the targets (e.g. date vs hall), and positive and negative outcomes (e.g. compliment vs rejection) the associated attributes. High social anxious women (N=32) showed the predicted deterioration of task performance if the required responses switched from compatible to incompatible with the idea that social situations are related to negative outcomes and vice versa, whereas the opposite was true for low anxious women (N=32). Thus a modified IAT seems a useful and highly flexible tool to implicitly assess complaint-specific dysfunctional associations and may be a valuable addition to the usual (explicit) self-report measures of patients' beliefs.

Masked fear words produce increased SCRs: an anomaly for Ohman's theory of pre-attentive processing in anxiety.

A. Ohman and J.J.F. Soares (1994) demonstrated that masked presentation of phobic pictures produces increased skin conductance responses (SCRs) in phobic subjects. A. Ohman (1993) explained this phenomenon in terms of a hypothetical "feature detector" that identifies physical characteristics of stimuli and activates the arousal system without involving significance evaluation or consciousness. By exposing spider phobics to spider words, general threat words, and neutral words instead of pictures, this explanation was tested. Words were presented both masked and unmasked while electrodermal activity was measured. Under unmasked conditions, SCRs were largest for spider words followed by general threat words, then neutral words. When masked, the difference between spider words and general threat words disappeared but SCRs remained significantly smaller for neutral words. It is concluded that activation of the arousal system by masked threat cues does not necessarily depend on their perceptual characteristics.

Metallothioneins (MTs) in marine molluscs.

The presence of MTs in marine molluscs was firstly hypothesized in oyster and in mussel during the seventies, however mussel's and oysters' MTs were completely purified and sequenced rather later. Already from the first studies it was evident that the purification of molluscan MTs was more difficult than in mammals. Mussel's MTs are characterized by the presence of a monomeric and a dimeric form. Several physiological and biochemical parameters can influence the concentration and the isolation of MT from molluscan tissues. Remarkable variations in MT isolation and quantification might depend on the purification and storage protocol. Because of possible artefacts due to the isolation procedure the establishment of a standard protocol for MT quantification in marine mollusc is still an important goal. In a few species the presence of very low molecular weight metal binding ligands has also been reported, in these cases it cannot be excluded that the native MT has been cleaved by the action of proteases. This review aims to report: 1) importance of a standard method for MT purification and quantification in molluscs; 2) distribution of MT among molluscan species; 3) data concerning oyster's and mussel's MTs which are the two more deeply investigated marine molluscs; 4) biotic and abiotic factors influencing MT concentration, and 5) biological role of MT and use of MT as a biochemical marker of heavy metal pollution.

Pseudoaneurysm of a lateral internal carotid artery in the middle ear.

We report a case where a 7-year-old girl suffered significant aural bleeding following myringotomy of the tympanic membrane. Investigations by computed tomography scan, carotid angiography, and magnetic resonance angiography showed a lateral aberrant internal carotid artery (LACI) with a little pseudoaneurysm in the middle ear. The anomaly of the internal carotid artery was supposed to be congenital, and the pseudoaneurysm was supposed to be traumatic, formed after incision into the wall of the artery. Considerations about diagnosis, symptoms, and treatment are discussed. The patient was treated by balloon embolization in the internal carotid artery without sequelae.

Levels of cellular glutathione and metallothionein affect the toxicity of oxidative stressors in an established carp cell line.

The comparative toxicity of a variety of oxidative stressors was studied in the epithelioma papulosum cyprini line from carp using the neutral red cytotoxicity assay. LC50's decreased in the order t-butylhydroperoxide > hydrogen peroxide > diquat > paraquat. The cytotoxicity of hydrogen peroxide was significantly reduced when the cells were grown in L-15 medium rather than MEM and this could be attributed to elevated cellular glutathione and metallothionein levels and higher activities of GSH-dependent detoxification systems. The protective effect of metallothionein in radical scavenging was demonstrated by decreased toxicity of the redox-cycling toxicants, diquat and menadione after metallothionein levels had been pre-induced by Cd-exposure. This study demonstrates the relationship between toxic effects of oxidative stressors and expression of detoxification systems in fish.

High-Level cognition in phobics: abstract anticipatory memory is associated with the attenuation of physiological reactivity to threat.

The extent to which anxious people benefit from exposure-based treatments seems to depend on the degree to which they activate their fear network during exposure. This study was designed to investigate whether the cognitive processing of threat in anxious individuals is dominated by abstract anticipatory memory, and whether this abstract memory mode is related to the incomplete activation of the fear network. Activation of the fear network was assessed during phobic exposure, as evidenced by the initial autonomic reaction. Spider phobics and controls were presented with a threatening imagery script. Half of them were exposed to a real-life spider. Spider phobics memorized relatively more abstract anticipatory descriptions than concrete sensory descriptions when compared with the control subjects. Only in phobic subjects. higher recognition of abstract anticipatory descriptions was inversely related to heart rate reactivity during exposure. A preferential memory mode for abstract information was related to an attenuated heart rate reactivity to threat in spider phobics. It is suggested that the preferential memory mode for abstract information may inhibit the activation of the subcortical affective memory system, which is crucial for the complete activation of the fear network. The absence of complete fear network activation may play a role in the persistence of anxiety disorders by hindering anxious individuals to learn that the stimuli they fear are not as dangerous as they assumed.

Illusory correlation and social anxiety.

An illusory correlation (IC) experiment examined the presence of a phobia-relevant covariation bias in the context of social anxiety. Low (n = 28) and high (n = 32) social anxious women were shown a series of slides comprising pictures of angry, happy and neutral faces which were randomly paired with either a shock, a siren or nothing. One half of the participants were shown women faces, whereas the other half were shown men faces. Participants indicated outcome expectancies on a trial by trial basis. After the experiment proper they estimated the contingencies of all slide/outcome combinations. Participants showed both an a priori and an a posteriori IC between angry faces and shock. This covariation bias was similar for men and women faces and independent of prior fear. The pattern of results is consistent with the idea that ICs arise from initial expectancies that survive extinction.

Comparative study of potential for bisphosphonates to damage gastric mucosa of rats.

Bisphosphonates have generally few clinical adverse effects, the most common being gastrointestinal disturbances. It is generally believed that bisphosphonates with a primary amine are more irritating to the gastrointestinal tract than those without a primary amine. The objective of this study was to compare the gastric irritation potential of an amino bisphosphonate (alendronate) to that of two nonamino bisphosphonates (risedronate and etidronate) in a rat model at pharmacologically equivalent and clinically relevant doses. The doses used were 1, 5, 10, and 30 mg/kg/day for alendronate and risedronate and 40, 200, 400, and 1200 mg/kg/day for etidronate. These doses represent 5-150 times the recommended clinical dose. The drugs were given orally, daily by gavage for four weeks. The gastric irritation potential was assessed by gross and microscopic evaluation of multiple sections of the stomach. This study showed that, at pharmacologically equivalent doses, the gastric irritation potential for alendronate is no greater than that for etidronate or risedronate.

Cognitive inhibition in phobia.

OBJECTIVES: The purpose of this study was to investigate whether cognitive bias for threat in anxious individuals may be attributed to a defective inhibition. DESIGN: It was investigated whether phobics and not non-phobics would show a defective inhibition of threat words as compared to neutral words. METHOD: Inhibition was measured by a negative priming task, which was administered to spider phobic participants (N = 29) and non-phobic controls (N = 31). RESULTS: The phobics did not show less negative priming of threatening information. Instead, they showed a general delay on all probe displays that were presented after threatening primes. CONCLUSION: Anxiety is related to defective inhibition of threat, in the sense that this inhibition consumes extra cognitive resources.

Phobia-related cognitive bias for pictorial and linguistic stimuli.

The purpose of this study was to examine whether anxiety-related cognitive bias for threat is stronger for threatening pictures than for threatening words. Spider-phobic participants (n = 31) and control participants (n = 33) performed a pictorial and linguistic spider Stroop task. Spider-phobic participants showed a marked bias for threat. However, this bias was similar for pictures and for words, although the spider-phobic group evaluated the pictures as being more aversive. The results suggest that automatic processing of threatening information in people with phobias is triggered in an on-off fashion, independent of subjective threat of the stimuli. This lack of distinction in automatic processing of weak and strong predictors of danger may be fundamental to the irrational nature of anxiety disorders.

Cognitive bias in spider fear and control children: assessment of emotional interference by a card format and a single-trial format of the stroop task.

The aim of the study was to clarify whether fear in children is related to a distorted cognitive processing of fear-related information. In anxious children, only a few studies of this bias were performed which yielded inconsistent results. Martin, Horder, and Jones (1992. Cognition and Emotion, 6(6), 479-486) found a bias for spider words in spider-fear children, using a card format of the Stroop task. However, by using a single-trial format of the Stroop task, we previously found that both anxious and control children favored the processing of threatening information (Kindt, Brosschot, & Everaerd, 1997. Journal of Experimental Child Psychology, 64, 79-97). In the present study, we administered both a card format and a single-trial format of the Stroop task to spider-fear and control children. In line with our previous results, a bias for spider words was observed in spider fear but also in control children, regardless of the format used. Furthermore, the processing biases assessed by the two formats did not correlate, which suggests that they measure different mechanisms and/or that one or both mechanisms are unstable. It is speculated that certain cognitive developmental deficits in regulating emotions may be a vulnerability factor in the etiology of anxiety disorders.

Cognitive processing bias of children in a real life stress situation and a neutral situation.

The aim of this study was to investigate whether nonclinically anxious children, like anxious adults, favor the processing of threatening or concern-related information. Two experiments, using an emotional Stroop task, were carried out in high anxious and low anxious children aged 8 to 9 to examine whether a medical stressor elicited a processing bias. Results indicated that, independently of the presence of the medical stressor, all children give high priority to the processing of information related to physical harm. Moreover, like anxious adults in other studies, high anxious children showed a processing bias for generally threatening information. This bias was absent in the vicinity of an acute stressor and it was only significant in girls. However, unlike low anxious adults, low anxious girls also showed this processing bias. These results are interpreted in terms of cognitive developmental differences in the ability to inhibit the processing of meaningful information.

Spider phobia questionnaire for children (SPQ-C): a psychometric study and normative data.

The purpose of this study was to develop a reliable and valid questionnaire to assess spider fear in children. The Spider Phobia Questionnaire for adults was adapted for children by simplifying items and by assessing situations relevant to children. The SPQ for children (SPQ-C) was administered to two non-clinical samples of children aged 8-12. The first sample consisted of 586 Ss who filled in the SPQ-C twice, with a retest interval of 6-7 weeks. Internal consistency and test-retest reliability were high. The second sample consisted of 669 children of which 28 spider phobic and 30 nonphobic girls were selected for the Behavioural Approach Test (BAT). The SPQ-C predicted BAT scores, thus supporting the validity of the questionnaire as a measure of spider fear. Norms for the SPQ-C, based on the total sample of children, are provided.