Spatial and temporal processing biases in visual working memory in specific anxiety

BACKGROUND.One group of theories aiming at providing a framework explaining the etiology, maintenance and phenomenology of anxiety disorders is classified as cognitive models of anxiety. These approaches assume that distortions in specific levels of information processing are relevant for the onset and maintenance of the disorder. A detailed knowledge about the nature of these distortions would have important implications for the therapy of anxiety, as the implementation of confrontative or cognitive elements precisely fitting the distortions might enhance efficacy. Still, these models and related empirical evidence provide conflicting assumptions about the nature of disorder-linked processing distortions. Many cognitive models of anxiety (e.g., Fox, Russo, & Dutton, 2002; Mathews & Mackintosh, 1998; Williams, Watts, MacLeod, & Mathews, 1997) postulate that anxiety-linked biases of attention imply hypervigilance to threat and distractibility from other stimuli in the presence of feared materials. This is convincingly confirmed by various experimentalclinical studies assessing attention for threat in anxious participants compared to non-anxious controls (for a review, seeMathews &MacLeod, 2005). In contrast, assumptions concerning anxiety-linked biased memory for threat are less convincing; based on the shared tendency for avoidance of deeper elaboration in anxiety disorders, some models predict memory biases only for implicit memory tasks (Williams et al., 1997) or even disclaim the relevance of memory in anxiety at all (e.g., Mogg, Bradley, Miles, & Dixon, 2004). Other theories restrict the possibility of measuring disorder-specific memory biases to tasks that require merely perceptual encoding of the materials instead of verbal-conceptual memory (e.g., Fox et al., 2002; Mathews &Mackintosh, 1998). On the one hand, none of these models has integrated all the inconsistencies in empirical data on the topic. On the other hand, the numerous empirical studies on memory in anxiety that have been conducted with varying materials, anxiety disorders, encoding and retrieval conditions do not allow final conclusions about the prerequisites for finding memory biases (for a review, see MacLeod & Mathews, 2004). A more detailed investigation of the complete spectrum of memory for threat utilizing carefully controlled variations of depth of encoding and materials is needed. In view of these inconsistencies, it is all the more surprising that one important part of this spectrum has so far remained completely uninvestigated: visual working memory (VWM). No study has ever differentially addressed VWM for threat in anxious vs. nonanxious participants and none of the cognitive models of anxiety provides any predictions concerning this stage of information processing. Research on cognitive biases in anxiety has thus far only addressed the two extremes of the processing continuum: attention and longer-term memory. In between, a gap remains, the bridging of which might bring us closer to defining the prerequisites of memory biases in anxiety. As empirical research has provided substantial and coherent knowledge concerning attention in anxiety, and as attention and VWM are so closely linked (see, for instance, Cowan, 1995), the thorough investigation of VWM may provide important clues for models of anxiety. Is anxiety related to VWM biases favoring the processing of threatening information, or does the avoidance presumed by cognitive models of anxiety already begin at this stage? RESEARCH AIMS. To investigate the relevance of biased VWM in anxiety, the present research focused in eight experiments on the following main research questions: (1) Is threat preferably stored in VWM in anxious individuals? (2) Does threat preference occur at the cost of the storage of other items, or is extra storage capacity provided? (3) Would the appearance of threat interrupt ongoing encoding of non-threatening items? (4) Does prioritized encoding of threat in anxiety occur strategically or automatically? (5) Are disorder-specific VWM biases also materials-specific? (6) Are VWM biases in anxiety modifiable through cognitive-behavioral therapy? METHODS. In Experiments 1-4, a spatial-sequential cueing paradigm was used. A subset of real-object display items was successively cued on each trial by a sudden change of the picture background for 150 ms each. After the cueing, one of the display pictures was hidden and probed for a memory test. On most trials, a cued item was tested, and memory accuracy was determined depending on the item’s position within the cue string and depending on its valence. In some cases, memory for an uncued item was tested. Experiment 1 and 2 were directed at discovering whether spider fearfuls and non-anxious controls would differ with respect to the accuracy in memorizing cued spiders and uncued spiders and, thus, reveal disorder-specific biases of VWM. In addition, the question whether the presence of a spider image is related to costs for the memorization of other images was tested. Experiment 3 addressed whether any disorder-specific VWM biases found earlier were specific to the feared spiders. Therefore, the critical stimuli here were a snake and a spider. Participants were spider fearfuls and non-anxious controls, both without snake anxiety. In Experiment 4, it was tested whether disorder-specific biases found in Experiment 1 and 2 were modifiable through cognitive-behavioral treatment. The critical stimulus was a spider image. Spider fearfuls were tested three times. Half of them received a cognitive-behavioral intervention after the first test, the other half only after the second test. In two additional experiments, VWM was assessed with a change-detection paradigm. The main aim was to clarify whether disorder-specific effects found in the previous experiments were associated with automatic or with strategic selective encoding of threatening materials, and whether any group differences in spider change detection were materials-specific to spiders, but not to snakes. In Experiment 5, several images were presented simultaneously in a study display for either 100 or 500 milliseconds. After a short interruption, a test display was presented including either the same items as the first one or one changed item. Participants’ accuracy in determining whether displays were the same or different was measured depending on the valence of the changed item, set size, and presentation time of the display. There were trials with and without spiders. If a change was made, it could involve either a non-spider or a spider item. Of specific interest was the condition in which a spider image was presented initially, but not in the test phase, as noticing this specific change would require storage of that image in VWM. Would group differences be particularly pronounced in the shorter encoding condition suggesting automatic encoding of threat, or would they occur in the longer encoding condition, suggesting strategic encoding of spiders? In Experiment 6, change detection accuracy for spiders vs. snakes was tested. The participants in both experiments were spider fearfuls vs. controls, but those of Experiment 6 were additionally required to lack snake anxiety. Moreover, a temporal VWM paradigm - an attentional blink task - was applied to assess whether a biased encoding of spider images in spider fearfuls would occur at the expense of non-threatening items undergoing concurrent processing, and whether this effect was specific to spiders, but not to snakes. Series of real-object pictures were presented at rates of 80 ms at the display center. The observer’s task was to identify and report the two target pictures indicated by a brighter background. In Experiment 7, the first target always depicted a neutral item. The valence of the second target was varied - either negative depicting a spider, positive, or neutral. Participants varied with respect to their spider anxiety. In Experiment 8, spider fearfuls and non-anxious controls, both without snake anxiety, were tested. The experiment was nearly the same as the previous one, but two negative target types were tested: disorder-relevant spiders and negative but not feared snakes. Of specific interest was whether the appearance of a threatening target would reduce the report probability of the earlier attended target, indicating the interruption of its VWM encoding in favor of the threat item. RESULTS. (1) Both anxious and non-anxious controls, showed VWM advantages for negative materials such as spider or snake images. (2) In addition, there were disorderspecific VWM biases: some effects were larger in spider fearfuls than in non-anxious controls and some effects occurred exclusively in spider fearfuls. (3) Group differences and, thus, disorder-specificity were particularly pronounced under competitive circumstances, that is, under the condition of numerous stimuli competing for processing resources: when only little orientation time was allowed, when only little time was provided for selecting and encoding items from a crowd, and when VWMfor the critical item required reflexive instead of voluntary attention. (4) Pronounced memory for task-relevant, voluntarily attended spiders was related to difficulties in disengaging attention from these items in the fearful group, reflected in reduced memory accuracy for the item following it. (5) Disorder-specific VWM biases seem to be based on attentional biases to threatening materials resulting in a very quick, automatic memory consolidation. However, this preferential encoding was not at the cost of neutral materials currently undergoing encoding processes. (6) All disorder-specific VWM biases occured only with fear-related materials, not with other negative materials. (7) Automatic and highly disorder-specific fear-related VWM biases – but not strategic VWM biases occuring in both groups - were modifiable through cognitive-behavioral intervention. CONCLUSIONS. This work provides additional information about informationprocessing distortions related to specific anxiety. With the experimental investigation of biased VWM, this work has been performed to fill a gap within research on cognitive biases in anxiety. Moreover, this dissertation contributes to cognitive theories of anxiety by proposing several recommendations for refinements of current theoretical approaches. Most important, it was suggested to extend existing models by a more detailed consideration of attention and memory. In view of numerous previous empirical studies on the topic and the conclusions of this dissertation, a differentiation of the attentional engagement and disengagement component appears inevitable. Even more important, in view of the data presented here predictions concerning VWM for threatening materials need to be taken into account. In addition, suggestions are provided for the differential consideration of biases occuring from prepotent threat value of negative stimuli vs. individual threat value. A proposal for a cognitive model of anxiety extended by all these aspects is provided to serve as an invitation of further research in the investigation of the nature of memory biases in anxiety disorders. REFERENCES: Cowan, N. (1995). Attention and Memory. An integrated framework.New York: Oxford University Press. Fox, E., Russo, R., & Dutton, K. (2002). Attentional bias for threat: Evidence for delayed disengagement from emotional faces. Cognition and Emotion, 16, 355-379. MacLeod, C., & Mathews, A. (2004). Selective memory effects in anxiety disorders: An overview of research findings and their implications. In D. Reisberg & P. Hertel (eds.), Memory and Emotion. Oxford: Oxford University Press. Mathews, A., & Mackintosh, B. (1998). A cognitive model of selective processing in anxiety. Cognitive Therapy and Research, 22 (6), 539-560. Mathews, A., & MacLeod, C. (2005). Cognitive vulnerability to emotional disorders. Annual Review of Clinical Psychology, 1, 167-195.Mathews, Mogg, May, & Eysenck (1989). Mogg, K., Bradley, B.P., Miles, F., & Dixon, R. (2004). Time course of attentional bias for threat scenes: Testing the vigilance avoidance hypothesis. Cognition and Emotion, 18(5), 689-700. Williams, J.M.G., Watts, F.N., MacLeod, C., & Mathews, A. (1997). Cognitive psychology and emotional disorders. Chichester: John Wiley

Trait anxiety is associated with hidden state inference during aversive reversal learning

Updating beliefs in changing environments can be driven by gradually adapting expectations or by relying on inferred hidden states (i.e. contexts), and changes therein. Previous work suggests that increased reliance on context could underly fear relapse phenomena that hinder clinical treatment of anxiety disorders. We test whether trait anxiety variations in a healthy population influence how much individuals rely on hidden-state inference. In a Pavlovian learning task, participants observed cues that predicted an upcoming electrical shock with repeatedly changing probability, and were asked to provide expectancy ratings on every trial. We show that trait anxiety is associated with steeper expectation switches after contingency reversals and reduced oddball learning. Furthermore, trait anxiety is related to better fit of a state inference, compared to a gradual learning, model when contingency changes are large. Our findings support previous work suggesting hidden-state inference as a mechanism behind anxiety-related to fear relapse phenomena

Trait anxiety is associated with hidden state inference during aversive reversal learning

Updating beliefs in changing environments can be driven by gradually adapting expectations or by relying on inferred hidden states (i.e. contexts), and changes therein. Previous work suggests that increased reliance on context could underly fear relapse phenomena that hinder clinical treatment of anxiety disorders. We test whether trait anxiety variations in a healthy population influence how much individuals rely on hidden-state inference. In a Pavlovian learning task, participants observed cues that predicted an upcoming electrical shock with repeatedly changing probability, and were asked to provide expectancy ratings on every trial. We show that trait anxiety is associated with steeper expectation switches after contingency reversals and reduced oddball learning. Furthermore, trait anxiety is related to better fit of a state inference, compared to a gradual learning, model when contingency changes are large. Our findings support previous work suggesting hidden-state inference as a mechanism behind anxiety-related to fear relapse phenomena

Reduction of aversive learning rates in Pavlovian conditioning by angiotensin II antagonist losartan: a randomized controlled trial

Background: Angiotensin receptor blockade has been linked to aspects of aversive learning and memory formation and to the prevention of posttraumatic stress disorder symptom development. Methods: We investigated the influence of the angiotensin receptor blocker losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized, placebo-controlled design, we tested 45 (18 female) healthy volunteers during a baseline session, after application of losartan or placebo (drug session), and during a follow-up session. During each session, participants engaged in a task in which they had to predict the probability of an electrical stimulation on every trial while the true shock contingencies switched repeatedly between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. Results: Acute administration of losartan significantly reduced participants’ adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates in the losartan group during the drug session compared with baseline. The 50-mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out a general reduction in attention and engagement. Decreased adjustment of aversive expectations was maintained at a follow-up session 24 hours later. Conclusions: This study shows that losartan acutely reduces Pavlovian learning in aversive environments, thereby highlighting a potential role of the renin-angiotensin system in anxiety development

Acute angiotensin II receptor blockade facilitates parahippocampal processing during memory encoding in high-trait-anxious individuals

Background Angiotensin II receptor blockers (ARBs) have been associated with preventing posttraumatic stress disorder symptom development and improving memory. However, the underlying neural mechanisms are poorly understood. This study investigated ARB effects on memory encoding and hippocampal functioning that have previously been implicated in posttraumatic stress disorder development. Methods In a double-blind randomized design, 40 high-trait-anxious participants (33 women) received the ARB losartan (50 mg) or placebo. At drug peak level, participants encoded images of animals and landscapes before undergoing functional magnetic resonance imaging, where they viewed the encoded familiar images and unseen novel images to be memorized and classified as animals/landscapes. Memory recognition was assessed 1 hour after functional magnetic resonance imaging. To analyze neural effects, whole-brain analysis, hippocampus region-of-interest analysis, and exploratory multivariate pattern similarity analysis were employed. Results ARBs facilitated parahippocampal processing. In the whole-brain analysis, losartan enhanced brain activity for familiar images in the parahippocampal gyrus (PHC), anterior cingulate cortex, and caudate. For novel images, losartan enhanced brain activity in the PHC only. Pattern similarity analysis showed that losartan increased neural stability in the PHC when processing novel and familiar images. However, there were no drug effects on memory recognition or hippocampal activation. Conclusions Given that the hippocampus receives major input from the PHC, our findings suggest that ARBs may modulate higher-order visual processing through parahippocampal involvement, potentially preserving intact memory input. Future research needs to directly investigate whether this effect may underlie the preventive effects of ARBs in the development of posttraumatic stress disorder

Investigating d-cycloserine as a potential pharmacological enhancer of an emotional bias-learning procedure

The partial NMDA receptor agonist d-cycloserine (DCS) may enhance psychological therapies. However, its exact mechanism of action is still being investigated. Cognitive Bias Modification (CBM) techniques allow isolation of cognitive processes and thus investigation of how they may be affected by DCS. We used a CBM paradigm targeting appraisals of a stressful event (CBM-App) to investigate whether DCS enhanced the modification of appraisal, and whether it caused greater reduction in indices of psychopathology. Participants received either 250mg of DCS (n = 19) or placebo (n = 19). As a stressor task, participants recalled a negative life event, followed by positive CBM-App training. Before and after CBM-App, appraisals and indices of psychopathology related to the stressor were assessed. CBM-App successfully modified appraisals, but DCS did not affect appraisals post-training. There were no post-training group differences in frequency of intrusions. Interestingly, DCS led to a greater reduction in distress and impact on state mood from recalling the event, and lower distress post-training was associated with fewer intrusions. Therefore, DCS may affect emotional reactivity to recalling a negative event when combined with induction of a positive appraisal style, but via a mechanism other than enhanced learning of the appraisal style

Brain activity measured by functional brain imaging predicts breathlessness improvement during pulmonary rehabilitation

Background Chronic breathlessness in chronic obstructive pulmonary disease (COPD) is effectively treated with pulmonary rehabilitation. However, baseline patient characteristics predicting improvements in breathlessness are unknown. This knowledge may provide better understanding of the mechanisms engaged in treating breathlessness and help to individualise therapy. Increasing evidence supports the role of expectation (ie, placebo and nocebo effects) in breathlessness perception. In this study, we tested functional brain imaging markers of breathlessness expectation as predictors of therapeutic response to pulmonary rehabilitation, and asked whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulated any predictive model. Methods Data from 71 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation were analysed (ID: NCT01985750). Baseline variables, including brain-activity, self-report questionnaires responses, clinical measures of respiratory function and drug allocation were used to train machine-learning models to predict the outcome, a minimally clinically relevant change in the Dyspnoea-12 score. Results Only models that included brain imaging markers of breathlessness-expectation successfully predicted improvements in Dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine was independently associated with breathlessness improvement. Models that included only questionnaires and clinical measures did not predict outcome (sensitivity 0.68, specificity 0.2). Conclusions Brain activity to breathlessness related cues is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is key in breathlessness perception. Manipulation of the brain’s expectation pathways (either pharmacological or non-pharmacological) therefore merits further testing in the treatment of chronic breathlessness

Ärztliche Gesundheitsbildung in Schulen – ein wichtiger Beitrag zur Steigerung der HPV-Impfmotivation

Fünfzehn Jahre nach Zulassung der Impfung gegen Humane Papillomviren (HPV) für Heranwachsende sind die Impfquoten im Vergleich zu anderen von der STIKO empfohlenen Impfungen im Säuglings- und Kleinkindalter sehr niedrig. In den Jahren 2017 – 2021 führte die Ärztliche Gesellschaft zur Gesundheitsförderung e. V. (ÄGGF) eine Vielzahl von Veranstaltungen durch, in denen HPV und die zugehörige Impfung Thema waren. Der Beitrag fasst Erkenntnisse aus vier evaluierten Projekten der ÄGGF zusammen, die im schulischen Setting durchgeführt wurden und sich an Schülerinnen und Schüler, Eltern/Erziehungsberechtigte und Lehrkräfte richteten.Peer Reviewe

Stratification of MDD and GAD patients by resting state brain connectivity predicts cognitive bias

Patients with Generalized Anxiety Disorder (GAD) and Major Depressive Disorder (MDD) show between-group comorbidity and symptom overlap, and within-group heterogeneity. Resting state functional connectivity might provide an alternate, biologically informed means by which to stratify patients with GAD or MDD. Resting state functional magnetic resonance imaging data were acquired from 23 adults with GAD, 21 adults with MDD, and 27 healthy adult control participants. We investigated whether within- or between-network connectivity indices from five resting state networks predicted scores on continuous measures of depression and anxiety. Successful predictors were used to stratify participants into two new groups. We examined whether this stratification predicted attentional bias towards threat and whether this varied between patients and controls. Depression scores were linked to elevated connectivity within a limbic network including the amygdala, hippocampus, VMPFC and subgenual ACC. Patients with GAD or MDD with high limbic connectivity showed poorer performance on an attention-to-threat task than patients with low limbic connectivity. No parallel effect was observed for control participants, resulting in an interaction of clinical status by resting state group. Our findings provide initial evidence for the external validity of stratification of MDD and GAD patients by functional connectivity markers. This stratification cuts across diagnostic boundaries and might valuably inform future intervention studies. Our findings also highlight that biomarkers of interest can have different cognitive correlates in individuals with versus without clinically significant symptomatology. This might reflect protective influences leading to resilience in some individuals but not others

The effect of d-cycloserine on brain processing of breathlessness over pulmonary rehabilitation: an experimental medicine study

Research questionPulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial N-methyl-d-aspartate (NMDA)-receptor agonistd-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.Methods72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ClinicalTrials.govidentifier:NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250 mgd-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences betweend-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions. An exploratory analysis determined the interaction with breathlessness anxiety.ResultsNo difference betweend-cycloserine and placebo groups was observed across the primary or secondary outcome measures.d-cycloserine was shown instead to interact with changes in breathlessness anxiety to dampen reactivity to breathlessness cues. Questionnaire and measures of respiratory function showed no group difference. This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power.ConclusionAlthough increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial ofd-cycloserine would not be worthwhile