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Background Interpretation biases (IBs) are central in panic disorder, and there is rich evidence showing that these are correlated with and predictive of panic-relevant symptomatology. However, experimental studies are needed to examine the potential causal effects of IBs, as predicted by cognitive models. Methods Panic-related IBs were manipulated via a sentence-completion Cognitive Bias Modification-Interpretation (CBM-I) training. The sample included N = 112 healthy participants reporting moderate levels of fear of bodily sensations. Participants were randomly allocated to a positive, negative, or control CBM-I condition. To test the trainings’ effect on panic-relevant cognitive processing, IBs were assessed via proximal and distal measures. Symptom provocation tasks were applied to test transfer to panic-relevant symptomatology. Results Results on the proximal measure showed that positive CBM-I led to more positive IBs compared to negative, and control training. Further, positive CBM-I led to more positive IBs on the distal measure as compared to negative CBM-I. However, there were no differential training effects on panic-related symptomatology triggered via the provocation tasks. Conclusion The findings indicate a limited generalization of the effects of CBM-I on IBs and panic-related symptoms. Potential means to improve generalization, such as applying more nuanced measures and combining CBM-I with psychoeducation are discussed.

The angiotensin receptor blocker losartan has been linked to aspects of aversive learning such as fear acquisition and extinction, inhibition of aversive learning rates and reduced post-traumatic stress disorder (PTSD) symptoms. Here, we investigate the influence of losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized placebo-controlled design, we tested 45 healthy volunteers during a baseline session (session 1), after application of losartan or placebo (session 2) and during a follow-up session (session 3). On each session, participants engaged in a task where they had to predict the likelihood of an electrical stimulation on every trial while the true shock contingencies repeatedly switched between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. 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 on the drug session compared to baseline. The 50mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out general reduction in attention and engagement. Decreased adjustment of aversive expectations to low-to-high, but not high-to-low, threat change was maintained on a follow up session 24hrs later, suggesting a possible role of losartan in prevention of formation of aversive associations on longer time scales.

Background According to major cognitive accounts of panic disorder, bodily sensations can lead to automatic activation of an associative fear network, potentially triggering a cascade of cognitive, emotional, and physiological responses culminating in a panic attack. However, the evidence for the automatic associations assumed by these models is mixed. This may reflect the heterogeneous nature of panic disorder, in that the relative importance of different bodily sensations and symptoms varies between individuals. The current study aimed to test this possibility via measuring the associations between three different sets of panic symptoms (cognitive, respiratory, cardiac) and scores on three symptom-specific single target implicit association tests (STIATs). Methods A total of 226 unselected female participants aged 18–35 completed the STIATs as well as questionnaires assessing panic symptoms and related measures in a web-based study. Results Only limited evidence was found to support the idea of specific associations between STIAT stimuli sets and their related panic symptoms. Exploratory analyses indicated that there were only associations between STIAT scores and panic-relevant questionnaires amongst those participants who had experienced a panic attack in the previous 6 months. Conclusions The results have implications for measuring panic-relevant associations and understanding their role in panic disorder.

Neuroimaging studies point to neurostructural abnormalities in youth with anxiety disorders. Yet, findings are based on small-scale studies, often with small effect sizes, and have limited generalizability and clinical relevance. These issues have prompted a paradigm shift in the field towards highly powered (i.e., big data) individual-level inferences, which are data-driven, transdiagnostic, and neurobiologically informed. Here, we built and validated neurostructural machine learning (ML) models for individual-level inferences based on the largest-ever multi-site neuroimaging sample of youth with anxiety disorders (age: 10-25 years, N=3,343 individuals from 32 global sites), as compiled by three ENIGMA Anxiety Working Groups: Panic Disorder (PD), Generalized Anxiety Disorder (GAD), and Social Anxiety Disorder (SAD). ML classifiers were trained on MRI-derived regional measures of cortical thickness, surface area, and subcortical volumes to classify patients and healthy controls (HC) for each anxiety disorder separately and across disorders (transdiagnostic classification). Modest, yet robust, classification performance was achieved for PD vs. HC (AUC=0.62), but other disorder-specific and transdiagnostic classifications were not significantly different from chance. However, above chance-level transdiagnostic classifications were obtained in exploratory subgroup analyses of male patients vs. male HC, unmedicated patients vs. HC, and patients with low anxiety severity vs. HC (AUC 0.59-0.63). The above chance-level classifications were based on plausible and specific neuroanatomical features in fronto-striato-limbic and temporo-parietal regions. This study provides a realistic estimate of classification performance in a large, ecologically valid, multi-site sample of youth with anxiety disorders, and may as such serve as a benchmark.

Accumulating evidence suggests that cognitive training may enhance well-being. Yet, mixed findings imply that individual differences and training characteristics may interact to moderate training efficacy. To investigate this possibility, the current paper describes a protocol for a data-driven individual-level meta-analysis study aimed at developing personalized cognitive training. To facilitate comprehensive analysis, this protocol proposes criteria for data search, selection and pre-processing along with the rationale for each decision. Twenty-two cognitive training datasets comprising 1544 participants were collected. The datasets incorporated diverse training methods, all aimed at improving well-being. These training regimes differed in training characteristics such as targeted domain (e.g., working memory, attentional bias, interpretation bias, inhibitory control) and training duration, while participants differed in diagnostic status, age and sex. The planned analyses incorporate machine learning algorithms designed to identify which individuals will be most responsive to cognitive training in general and to discern which methods may be a better fit for certain individuals.

Background: Glucocorticoid (GC) administration prior to exposure-based cognitive-behavioural therapy (CBT) has emerged as a promising approach to facilitate treatment outcome in anxiety disorders. Further components relevant for improved CBT efficacy include raised endogenous GCs and reductions in information-processing biases to threat. Aims: To investigate hydrocortisone as an adjunct to CBT for spider fear and the modulating role of threat bias change and endogenous short-term and long-term GCs for treatment response. Methods: Spider-fearful individuals were randomized to receiving either 20 mg of hydrocortisone ( n = 17) or placebo ( n = 16) one hour prior to single-session predominantly computerised exposure-based CBT. Spider fear was assessed using self-report and behavioural approach measures at baseline, 1-day and 1-month follow-up. Threat processing was assessed at baseline and 1-day follow-up. Cortisol and cortisone were analysed from hair and saliva samples at baseline. Results/outcomes: Self-report, behavioural and threat processing indices improved following CBT. Hydrocortisone augmentation resulted in greater improvement of self-report spider fear and stronger increase in speed when approaching a spider, but not on threat bias. Neither threat bias nor endogenous GCs predicted symptom change, and no interactive effects with hydrocortisone emerged. Preliminary evidence indicated higher hair cortisone as predictor of a stronger threat bias reduction. Conclusions/interpretation: Our data extend earlier findings by suggesting that GC administration boosts the success of exposure therapy for specific fear even with a low-level therapist involvement. Future studies corroborating our result of a predictive hair GC relationship with threat bias change in larger clinical samples are needed.

Background: The optimisation of learning has long been a focus of scientific research, particularly in relation to improving psychological treatment and recovery of brain function. Previously, partial N-methyl-D-aspartate agonists have been shown to augment reward learning, procedural learning and psychological therapy, but many studies also report no impact of these compounds on the same processes. Aims: Here we investigate whether administration of an N-methyl-D-aspartate partial agonist (D-cycloserine) modulates a previously unexplored process – tactile perceptual learning. Further, we use a longitudinal design to investigate whether N-methyl-D-aspartate-related learning effects vary with time, thereby providing a potentially simple explanation for apparent mixed effects in previous research. Methods: Thirty-four volunteers were randomised to receive one dose of 250 mg D-cycloserine or placebo 2 h before tactile sensitivity training. Tactile perception was measured using psychophysical methods before and after training, and 24/48 h later. Results: The placebo group showed immediate within-day tactile perception gains, but no further improvements between-days. In contrast, tactile perception remained at baseline on day one in the D-cycloserine group (no within-day learning), but showed significant overnight gains on day two. Both groups were equivalent in tactile perception by the final testing – indicating N-methyl-D-aspartate effects changed the timing, but not the overall amount of tactile learning. Conclusions: In sum, we provide first evidence for modulation of perceptual learning by administration of a partial N-methyl-D-aspartate agonist. Resolving how the effects of such compounds become apparent over time will assist the optimisation of testing schedules, and may help resolve discrepancies across the learning and cognition domains.

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.

Background Cognitive models of panic disorder (PD) highlight the role of panic-related associations and interpretations. However, results are mixed and rely on specific measures. This study examined panic-related associations and interpretations using established and new paradigms in individuals varying on anxiety sensitivity (AS). Methods Associations were measured using a priming task and a novel Single Target Implicit Association Test (STIAT); interpretations were assessed using the Interpretation Bias Questionnaire (IBQ) and a novel Scrambled Sentences Task (SST). Symptoms were assessed via a provocation task (Straw Breathing Task, SBT). Results Panic-related interpretations correlated with AS and other PD-related measures. Of the association tasks, only the priming task correlated with one of the other PD-related measures. Panic-related interpretations assessed via the SST, but not priming, STIAT, and IBQ, predicted SBT reactivity. The relationship between AS and SBT reactivity was mediated by panic-related interpretations. Conclusions Our data provide support for panic-related interpretations as an important cognitive mechanism.

BackgroundChronic breathlessness in 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, helping to individualise therapy. Increasing evidence supports the role of expectation (i.e. 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 whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulates any predictive model.MethodsData from 72 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation was 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.FindingsOnly 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).InterpretationBrain 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) merits further testing in the treatment of chronic breathlessness.FundingThis work was supported by the JABBS FoundationResearch in contextEvidence before the studyDespite considerable research we still do not know which patient characteristics predict clinical improvements in breathlessness following pulmonary rehabilitation. Recent evidence suggests that the brain processes associated with breathlessness-expectation play an important contributory role in breathlessness severity. However, this has never been examined as a predictor of pulmonary rehabilitation outcome. The ability to predict outcomes has a number of potential benefits, including identifying targets for personalised medicine and the better allocation of scare healthcare resources via parallel care pathways.Added value of the studyThis study analysed data from a longitudinal experimental medicine study of 71 patients with COPD over a course of pulmonary rehabilitation, that used functional magnetic resonance imaging testing breathlessness-expectation mechanisms in the brain. Participants were randomised in a double-blind procedure to receive either 250mg oral D-cycloserine or a matched placebo. Using baseline variables to train machine learning models we revealed that only models containing brain markers of breathlessness-expectation successfully predicted improvements in dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine use was independently associated with breathlessness improvements. Models that only contained questionnaire and clinical measure did not predict outcome (sensitivity 0.68, specificity 0.2).Implications of all the available evidenceThese findings are the first evidence that breathlessness-expectation related brain activity is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is a key mechanism in breathlessness perception and that the manipulation of the brain’s expectation pathways merits further testing as a novel therapeutic approach for breathlessness.

BackgroundPulmonary 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 NMDA-receptor agonist, D-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 (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg D-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between D-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.ResultsNo difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference.ConclusionsThis is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D-cycloserine would not be worthwhile.Key MessagesWhat is the key question?Does the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity?What is the bottom line?Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation.Why read on?This study highlights both the value of functional magnetic resonance imaging in “de-risking” expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness.

The angiotensin-II antagonist losartan is a promising candidate that has enhanced extinction in a post-traumatic stress disorder (PTSD) animal model and was related to reducing PTSD symptom development in humans. Here, we investigate the neurocognitive mechanisms underlying these results, testing the effect of losartan on data-driven and contextual processing of traumatic material, mechanisms proposed to be relevant for PTSD development. In a double-blind between-subject design, 40 healthy participants were randomised to a single oral dose of losartan (50 mg) or placebo, 1 h before being exposed to distressing films as a trauma analogue while heart rate (HR) was measured. Peritraumatic processing was investigated using blurry picture stimuli from the films, which transformed into clear images. Data-driven processing was measured by the level of blurriness at which contents were recognised. Contextual processing was measured as the amount of context information retrieved when describing the pictures’ contents. Negative-matched control images were used to test perceptual processing of peripheral trauma-cues. Post-traumatic stress symptoms were assessed via self-report questionnaires after analogue trauma and an intrusion diary completed over 4 days following the experiment. Compared to placebo, losartan facilitated contextual processing and enhanced detail perception in the negative-match pictures. During the films, the losartan group recorded lower HR and higher HR variability, reflecting lower autonomic stress responses. We discuss potential mechanisms of losartan in preventing PTSD symptomatology, including the role of reduced arousal and increased contextual processing during trauma exposure, as well as increased threat-safety differentiation when encountering peripheral trauma-cues in the aftermaths of traumatic events.

Item does not contain fulltext Patients with panic disorder show abnormalities in threat processing and regulation, both on a behavioural and neural level. Better understanding of the underlying mechanisms could help to develop new treatment strategies. In this study, we investigated brain region activation in 18 patients with untreated panic disorder (PD) and 17 healthy controls (HC) during the processing of emotional faces with fearful, happy and neutral expressions, using functional MRI. The intensity of the expressions was either prototypically high, medium or low. PD patients showed significantly increased activity in the dorso-medial prefrontal cortex (dmPFC) in response to faces in general and specifically for happy faces. While HC showed a decreased amygdala response to medium/low fearful versus high fearful faces, this effect was not present in PD: amygdala activation was stable across all fearful faces in this group. Psycho-physiological interaction analyses indicated more negative connectivity between the amygdala and prefrontal areas in the PD group during the task. Amygdala activation in panic patients appears to be less sensitive to decreasing intensities of fearful facial expressions and salience monitoring areas were less active during fearful faces in general in this group. This suggests PD patients might avoid more extensive processing of fearful faces.

Background Current models of breathlessness often fail to explain disparities between patients' experiences of breathlessness and objective measures of lung function. While a mechanistic understanding of this discordance has thus far remained elusive, factors such as mood, attention and expectation have all been implicated as important modulators of breathlessness. Therefore, we have developed a model to better understand the relationships between these factors using unsupervised machine learning techniques. Subsequently we examined how expectation-related brain activity differed between these symptom-defined clusters of participants. Methods A cohort of 91 participants with mild-to-moderate chronic obstructive pulmonary disease (COPD) underwent functional brain imaging, self-report questionnaires and clinical measures of respiratory function. Unsupervised machine learning techniques of exploratory factor analysis and hierarchical cluster modelling were used to model brain–behaviour–breathlessness links. Results We successfully stratified participants across four key factors corresponding to mood, symptom burden and two capability measures. Two key groups resulted from this stratification, corresponding to high and low symptom burden. Compared with the high symptom burden group, the low symptom burden group demonstrated significantly greater brain activity within the anterior insula, a key region thought to be involved in monitoring internal bodily sensations (interoception). Conclusions This is the largest functional neuroimaging study of COPD to date, and is the first to provide a clear model linking brain, behaviour and breathlessness expectation. Furthermore, it was possible to stratify participants into groups, which then revealed differences in brain activity patterns. Together, these findings highlight the value of multimodal models of breathlessness in identifying behavioural phenotypes and for advancing understanding of differences in breathlessness burden., European Respiratory Journal, 58 (5), ISSN:0903-1936, ISSN:1399-3003

Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA‐Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA‐Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA‐Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders., Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA‐Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA‐Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders.

Contains fulltext : 214596pub.pdf (Publisher’s version ) (Closed access) Contains fulltext : 214596pre.pdf (Author’s version preprint ) (Open Access) Background and objectives: In anxiety disorders, cognitive behavioural therapy (CBT) improves information-processing biases such as implicit fear evaluations and avoidance tendencies, which predicts treatment response. Thus, these cognitive biases might constitute important treatment targets. This study investigated (i) whether information-processing biases could be changed following single-session computerised CBT for spider fear, and (ii) whether this effect could be augmented by administration of D-cycloserine (DCS). Methods: Spider-fearful individuals were randomized to receiving either 250 mg of DCS (n = 21) or placebo (n = 17). Three hours after drug administration, they received single-session computerized CBT, characterized by psychoeducation and exposure elements. Spider fear was assessed using self-report, behavioural, and information processing (Extrinsic Affective Simon Task & Approach Avoidance Task) measures at baseline (before drug administration), post-treatment, 1-day, and 1-month follow-up. Results: Linear mixed-effects analyses indicated significant improvements on self-report and behavioural spider fear indices following CBT, but not on cognitive bias measures. There was no evidence of an augmentation effect of DCS on any outcome. Cognitive bias measures at 1-day were not predictive of 1-month follow-up spider fear in adjusted linear regression analyses. Limitations: Results might be biased by limited representativeness of the sample (high education and intelligence, largely Caucasian ethnicity, young age). The study was also only powered for detection of medium-sized DCS effects. Conclusions: These findings do not provide evidence for information-processing biases relating to treatment outcome following computerised CBT for spider fear or augmentation with DCS. 10 p.

Background The antihypertensive drug losartan has been shown to improve memory in humans as well as learning and fear extinction in rodent models, highlighting its potential to have similar synergistic effects on exposure-based cognitive behavioral therapy for anxiety disorders. This study investigated the effect of losartan on neural correlates of processing threat versus safety stimuli in highly anxious individuals to identify potential pathways of how the drug might facilitate psychological treatment. Methods Thirty healthy volunteers high in trait anxiety were randomly assigned to a single dose of losartan (50 mg) versus placebo before undergoing functional magnetic resonance imaging. We measured brain response to happy and fearful faces presented for 80 seconds to assess emotional processing and habituation over time. Results The placebo group showed similarly high left amygdala activation early on during presentation of fearful and happy faces, which decreased over time. In contrast, losartan reduced amygdala response to happy faces early on. In response to fearful faces, the drug prevented habituation, caused sustained amygdala activation, and led to increased activation in other brain areas associated with threat processing, such as the insula and putamen. Conclusions Our findings suggest two distinct effects of losartan on emotional processing, including an improvement of early discrimination of stimuli as threatening versus safe, and facilitation of threat processing. Both processes are known to be relevant for successful exposure, highlighting two potential pathways by which losartan might exert facilitative effects on psychological treatment.

Background: It has been suggested that the behavioural activation (BA) treatments for depression unfold their effects, at least partly, through changes in approach and avoidance tendencies. However, as yet, little research has examined the cognitive effects of these interventions. Aims: This study investigated the impact of a single session of BA on depressive symptomatology, self-reported avoidance, and behavioural approach and avoidance tendencies. Method: Forty-six patients with a diagnosis of Major Depression were recruited from primary care psychological therapies services and block randomized to either a single session of behavioural activation (n = 22) or waiting list control (n = 24) delivered by an unblinded therapist. Self-reports of symptoms and cognitive factors were assessed before and after the one-week intervention phase. Approach and avoidance behavioural tendencies were assessed using the Approach-Avoidance Task (AAT). Results: Data from 40 participants (n = 20 in each group) was available for analyses. Depressive symptoms significantly decreased, and activation significantly increased from before to after treatment in the treatment group, but not in the control group. Performance on the AAT showed a trend indicating increased approach to positive valence stimuli in the treatment group, but not in the control group. Mediational analyses indicated small indirect effects of self-reported change in activation as mediators of the effect of condition on symptoms. Conclusions: The findings suggest that a single session of BA can have significant effects on symptoms in clinically depressed patients. Results hint at the possibility that increased behavioural approach might mediate the effect of BA.

BackgroundChronic breathlessness profoundly affects quality of life for its sufferers. Often, reported breathlessness is inconsistent with airway pathophysiology and objective disease markers. While a mechanistic understanding of this discordance has thus far remained elusive, factors such as mood, attention and expectation have all been implicated as important perceptual modulators. Therefore, here we have developed a model capable of exploring these relationships aiding patient stratification and revealing clinically-relevant neuro-biomarkers.MethodsA cohort of 100 participants with mild-to-moderate chronic obstructive pulmonary disease (COPD) underwent a comprehensive assessment that included functional brain imaging while viewing and rating breathlessness-related word cues, self-report questionnaires and clinical measures.ResultsUsing an exploratory factor analysis across psychological and physiological measures, we identified two distinctive neuropsychological behavioural profiles that differed across four key factors corresponding to mood, symptom burden, and two capability measures. These profiles stratified participants into high and low symptom groups, which did not differ in spirometry values. The low symptom load group demonstrated greater FMRI activity to breathlessness-related word cues in the anterior insula.ConclusionsOur findings reveal two clear groups of individuals within our COPD cohort, divided by behavioural rather than clinical factors. Furthermore, indices of depression, anxiety, vigilance and perceived capability were linked to differences in brain activity within key regions thought to be involved in monitoring bodily sensations (interoception). These findings demonstrate the complex relationship between affect and interoceptive processing, providing the foundations for the development of targeted treatment programmes that harness clinical and symptom-relevant biomarkers.

ObjectiveDrugs targeting the N-Methyl-D-aspartic acid (NMDA) system and the ability to learn new associations have been proposed as potential adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment.MethodsUnmedicated patients with panic disorder were randomised to single-dose d-cycloserine (250mg; N=17) or matching placebo (N=16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces and amygdala response to threat. Clinical symptom severity was measured using self-report and clinician-rated scales the day before and after treatment, and at 1- and 6-months follow-up. Analysis was by intention-to-treat.ResultsOne day after treatment, threat bias for fearful faces and amygdala threat response were attenuated in the drug compared to the placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. D-cycloserine led to greater clinical recovery at 1-month follow-up (d-cycloserine 71% versus placebo 25%).DiscussionD-cycloserine-augmented single-session exposure therapy reduces amygdala threat response, and this effect predicts later clinical response. These findings highlight a neurocognitive mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate future development of adjunct treatments with CBT for anxiety disorders. (D-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov;NCT01680107)

Background Anxiety disorders are common and disabling conditions. First-line pharmacological treatment with selective-serotonin-reuptake inhibitors (SSRI) and psychological treatment with cognitive-behaviour therapy (CBT) are effective intervention approaches, but not all patients respond, and relapse rates remain relatively high. Aims To identify cognitive and neurobiological mechanisms of action of pharmacological and psychological standard-of-care treatments for anxiety disorders, to then logically derive potential add-on treatment ingredients that might serve to augment such effects. Method We summarise key published work that examined cognitive and neurobiological markers of anxiety disorders and the effects of SSRI and CBT on such parameters. We also discuss potential neuropsychological mechanisms of action of both treatments, and we suggest candidate add-on ingredients likely to improve such actions, based on their key effects. Results Anxiety disorders have been associated with hypervigilance for threat followed by an avoidance of deeper processing. Such effects appear to be underpinned by increased activation in brain areas involved in attention and monitoring, such as amygdala, insula, occipital cortex and dorsomedial prefrontal cortex, as well as alterations in areas implicated in emotion regulation, including lateral and ventral prefrontal cortex. Converging evidence suggests that both SSRI and CBT modulate cognitive bias and underlying functional abnormalities early during treatment, and that such changes moderate recovery from anxiety. Conclusions Pharmacological and psychological standard-of-care treatments for anxiety disorders seem to act by targeting cognitive bias early during treatment. A range of pharmacological and neurostimulation strategies known to impair fear memory reconsolidation or to improve fear extinction may have potential to improve the effects of psychological intervention. Such approaches might ultimately help to develop more effective, more economic treatment formats.

Item does not contain fulltext Objective: Threat-related attention bias figures prominently in contemporary accounts of the maintenance of anxiety disorders, yet longitudinal intervention research relating attention bias to anxiety symptom severity is limited. Capitalizing on recent advances in the conceptualization and measurement of attention bias, we aimed to examine the relation between attention bias, indexed using trial-level bias scores (TLBSs) to quantify temporal dynamics reflecting dysregulation of attentional processing of threat (as opposed to aggregated mean bias scores) and social anxiety symptom severity over the course of cognitive-behavioral therapy (CBT) and 1-month follow-up. Method: Adults with social anxiety disorder (N = 39) assigned to either yohimbine- or placebo-augmented CBT completed measures of attention bias and social anxiety symptom severity weekly throughout CBT (5 sessions) and at 1-week and 1-month posttreatment. Results: TLBSs of attention bias temporal dynamics showed stronger psychometric properties than mean aggregated scores and were highly interrelated, in line with within-subject temporal variability fluctuating in time between attentional overengagement and strategic avoidance from threat. Attention bias toward threat and temporal variability in attention bias (i.e., attentional dysregulation), but not attention bias away from threat, significantly reduced over the course of CBT. Cross-lag analyses revealed no evidence of a causal relation between reductions in attentional dysregulation leading to symptom severity reduction, or vice versa. Observed relations did not vary as a function of time. Conclusions: We found no evidence for attentional dysregulation as a causal mechanism for symptom reduction in CBT for social anxiety disorders. Implications for future research are discussed. 8 p.

Drugs targeting N-methyl- d -aspartate (NMDA) receptors and the ability to learn new associations have been proposed as adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d -cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d -cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment. Panic disorder patients were randomised to single-dose d -cycloserine (250 mg; N = 17) or matching placebo (N = 16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces (primary outcome) and amygdala response to threat (secondary outcome). Clinical symptom severity was measured the day before and after treatment, and at 1- and 6-months follow-up (secondary outcome). d -cycloserine was associated with greater clinical recovery at 1-month follow-up than placebo ( d -cyloserine 71% vs placebo 25%), with the placebo group matching the clinical gains of the d -cycloserine group during 6-months follow-up ( d -cycloserine 71% vs placebo 44%). One day after treatment, threat bias for fearful faces and amygdala threat response was lower in the drug compared to placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. While this experimental study is of a preliminary nature due to the limited sample size, these findings highlight a neurocognitive potential mechanism by which d -cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate development of combination treatments for anxiety. ( d -cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov; NCT01680107).

Exposure therapy is a first-line treatment for anxiety disorders but remains ineffective in a large proportion of patients. A proposed mechanism of exposure involves a form of inhibitory learning where the association between a stimulus and an aversive outcome is suppressed by a new association with an appetitive or neutral outcome. The blood pressure medication losartan augments fear extinction in rodents and might have similar synergistic effects on human exposure therapy, but the exact cognitive mechanisms underlying these effects remain unknown. In this study, we used a reinforcement learning paradigm with compound rewards and punishments to test the prediction that losartan augments learning from appetitive relative to aversive outcomes. Healthy volunteers (N=53) were randomly assigned to single-dose losartan (50mg) versus placebo. Participants then performed a reinforcement learning task which simultaneously probes appetitive and aversive learning. Participant choice behaviour was analysed using both a standard reinforcement learning model and by analysis of choice switching behaviour. Losartan significantly reduced learning rates from aversive events (losses) when participants were first exposed to the novel task environment, while preserving learning from positive outcomes. The same effect was seen in choice switching behaviour. Losartan enhances learning from positive relative to negative events. This effect may represent a computationally defined neurocognitive mechanism by which the drug could enhance the effect of exposure in clinical populations.

Exposure-based cognitive-behaviour therapy (CBT) for anxiety disorders is an effective intervention, but the brain mechanisms driving recovery are largely unknown. In this experimental medicine study, we investigated to what degree CBT affects neural markers of anxiety at an early stage of treatment, to identify dynamic mechanistic changes which might be crucial in the process of recovery as opposed to those seen following full treatment completion. In a randomised controlled trial, unmedicated patients with panic disorder either received four weekly sessions of exposure-based CBT (N = 14) or were allocated to a waiting group (N = 14). Symptom severity was measured before and after the intervention. During functional magnetic resonance imaging (fMRI), patients performed an emotion regulation task, either viewing negative images naturally, or intentionally down-regulating negative affect using previously taught strategies. Four-session CBT led to marked reductions in symptoms and 71% of patients reached recovery status (versus 7% in the control group). This intervention normalised brain hyperactivation previously seen in panic disorder, particularly in areas linked to threat monitoring, fear memory, and maladaptive emotion regulation, such as amygdala, dorsomedial and dorsolateral prefrontal cortex, and temporal gyrus. Our findings suggest that optimal treatment doses for panic disorder might be much lower than previously thought. Furthermore, this is the first study to show that neural markers of anxiety change very early during CBT, highlighting potential neural mechanisms that might drive clinical recovery. Such knowledge is important for the development of more compact combination treatments targeting these mechanisms more effectively. (Neural Effects of Cognitive-behaviour Therapy in Panic Disorder; clinicaltrials.gov; NCT03251235).

Despite its physiological and clinical relevance, the influence of hydrocortisone on specific kinds of learning remains relatively unexplored. We measured the effect of hydrocortisone on motor sequence and reward learning under non-stress conditions. For the study, 54 healthy young volunteers were randomly assigned to a dose of 20 mg hydrocortisone versus placebo. Participants performed two well-defined learning tasks. Hydrocortisone did not affect motor sequence or reward learning.

Background - Drugs targeting the N-Methyl-D-aspartic acid (NMDA) system and learning rates have been proposed as potential adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We therefore investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure therapy using a single-session testbed, to inform the optimal combination of this and similar agents with psychological treatment. Methods - This randomized double-blind study was run at a single location (university environment). Unmedicated patients with panic disorder received single-dose d-cycloserine (250mg; N=17) or matching placebo (N=16) 2hrs before one session of exposure therapy. Clinical symptom severity was measured using self-report and clinician-rated scales the day before and after treatment, and at 1- and 6-months follow-up. Neurocognitive markers were assessed one day after treatment, including two primary outcome measures threat bias for fearful faces (FDOT) and implicit panic associations (IAT) and a secondary outcome measure amygdala response to threat. Analysis was by intention-to-treat. Outcome - Threat bias (FDOT) reduced to a larger extent following d-cycloserine (CYC) versus placebo (PLAC) but failed to reach the corrected level of significance (p < 0·025) (mean difference -19·0, 95% CI -38·04 to -0·14; p=0·042, d=0·77). There were no significant drug effects on the IAT (mean difference -0·01, 95% CI -0·32 to 0·29; p=0·93, d=0·11). On the day after treatment, amygdala threat response was lower in the drug compared to the placebo group (mean difference -0·32, 95% CI -0·61 to -0·03; p=0·023, d=1·08), with lower magnitude predicting greater clinical improvement during follow-up across groups. D-cycloserine led to greater clinical recovery at 1-month follow-up (CYC 71% versus PLAC 25%, RR 2·55, CI 1·16-5·61, p=0·015). No serious side effects were reported. Interpretation - D-cycloserine-augmented single-session exposure therapy reduces amygdala response to threat, and this effect predicts later clinical response. These findings highlight a neurocognitive mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate future development of adjunct treatments with CBT for anxiety disorders. Trial Registration Number: clinicaltrials.gov, NCT01680107 Funding - Medical Research Council, Oxford University John-Fell-Fund (D-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov; NCT01680107). Declaration of Interest: AR and AN report no conflicts of interest. MB has received travel expenses from Lundbeck for attending conferences and has acted as a consultant for J&J. CH has received consultancy fees from Lundbeck, P1vital, J&J, Pfizer and Servier. Ethical Approval: Ethical approval was obtained from the South Central - Hampshire research ethics committee. All participants gave written informed consent.

The partial N-methyl-D-aspartate receptor agonist d-cycloserine may enhance psychological therapies. However, its exact mechanism of action is still being investigated. Cognitive bias modification techniques allow isolation of cognitive processes and thus investigation of how they may be affected by d-cycloserine. We used a cognitive bias modification paradigm targeting appraisals of a stressful event, Cognitive Bias Modification-Appraisal, to investigate whether d-cycloserine enhanced the modification of appraisal, and whether it caused greater reduction in indices of psychopathology. Participants received either 250 mg of d-cycloserine ( n=19) or placebo ( n=19). As a stressor task, participants recalled a negative life event, followed by positive Cognitive Bias Modification-Appraisal training. Before and after Cognitive Bias Modification-Appraisal, appraisals and indices of psychopathology related to the stressor were assessed. Cognitive Bias Modification-Appraisal successfully modified appraisals, but d-cycloserine did not affect appraisals post-training. There were no post-training group differences in frequency of intrusions. Interestingly, d-cycloserine 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, d-cycloserine 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.

BackgroundNegative cognitive bias and aberrant neural processing of emotional faces are trait-marks of depression. Yet it is unclear whether these changes constitute an endophenotype for depression and are also present in healthy individuals with hereditary risk for depression.MethodThirty healthy, never-depressed monozygotic (MZ) twins with a co-twin history of depression (high risk group: n = 13) or without co-twin history of depression (low-risk group: n = 17) were enrolled in a functional magnetic resonance imaging (fMRI) study. During fMRI, participants viewed fearful and happy faces while performing a gender discrimination task. After the scan, they were given a faces dot-probe task, a facial expression recognition task and questionnaires assessing mood, personality traits and coping strategies.ResultsHigh-risk twins showed increased neural response to happy and fearful faces in dorsal anterior cingulate cortex (ACC), dorsomedial prefrontal cortex (dmPFC), pre-supplementary motor area and occipito-parietal regions compared to low-risk twins. They also displayed stronger negative coupling between amygdala and pregenual ACC, dmPFC and temporo-parietal regions during emotional face processing. These task-related changes in neural responses in high-risk twins were accompanied by impaired gender discrimination performance during face processing. They also displayed increased attention vigilance for fearful faces and were slower at recognizing facial expressions relative to low-risk controls. These effects occurred in the absence of differences between groups in mood, subjective state or coping.ConclusionsDifferent neural response and functional connectivity within fronto-limbic and occipito-parietal regions during emotional face processing and enhanced fear vigilance may be key endophenotypes for depression.

Impairments in emotion regulation are thought to have a key role in the pathogenesis of anxiety disorders, but the neurobiological underpinnings contributing to vulnerability remain poorly understood. It has been a long-held view that exaggerated fear is linked to hyperresponsivity of limbic brain areas and impaired recruitment of prefrontal control. However, increasing evidence suggests that prefrontal–cortical networks are hyperactive during threat processing in anxiety disorders. This study directly explored limbic–prefrontal neural response, connectivity and heart-rate variability (HRV) in patients with a severe anxiety disorder during incidental versus intentional emotion regulation. During 3 Tesla functional magnetic resonance imaging, 18 participants with panic disorder and 18 healthy controls performed an emotion regulation task. They either viewed negative images naturally (Maintain), or they were instructed to intentionally downregulate negative affect using previously taught strategies of cognitive reappraisal (Reappraisal). Electrocardiograms were recorded throughout to provide a functional measure of regulation and emotional processing. Compared with controls, patients showed increased neural activation in limbic–prefrontal areas and reduced HRV during incidental emotion regulation (Maintain). During intentional regulation (Reappraisal), group differences were significantly attenuated. These findings emphasize patients’ ability to regulate negative affect if provided with adaptive strategies. They also bring prefrontal hyperactivation forward as a potential mechanism of psychopathology in anxiety disorders. Although these results challenge models proposing impaired allocation of prefrontal resources as a key characteristic of anxiety disorders, they are in line with more recent neurobiological frameworks suggesting that prefrontal hyperactivation might reflect increased utilisation of maladaptive regulation strategies quintessential for anxiety disorders.

OBJECTIVE: Acute administration of an antidepressant increases positive affective processing in healthy volunteers, an effect that may be relevant to the therapeutic actions of these medications. The authors investigated whether this effect is apparent in depressed patients early in treatment, prior to changes in mood and symptoms. METHOD: In a double-blind, placebo-controlled, between-groups randomized design, the authors examined the effect of a single 4-mg dose of the norepinephrine reuptake inhibitor reboxetine on emotional processing. Thirty-three depressed patients were recruited through primary care clinics and the community and matched to 31 healthy comparison subjects. Three hours after dosing, participants were given a battery of emotional processing tasks comprising facial expression recognition, emotional categorization, and memory. Ratings of mood, anxiety, and side effects were also obtained before and after treatment. RESULTS: Depressed patients who received placebo showed reduced recognition of positive facial expressions, decreased speed in responding to positive self-relevant personality adjectives, and reduced memory for this positive information compared to healthy volunteers receiving placebo. However, this effect was reversed in patients who received a single dose of reboxetine, despite the absence of changes in subjective ratings of mood or anxiety. CONCLUSIONS: Antidepressant drug administration modulates emotional processing in depressed patients very early in treatment, before changes occur in mood and symptoms. This effect may ameliorate the negative biases in information processing that characterize mood and anxiety disorders. It also suggests a mechanism of action compatible with cognitive theories of depression.

Seven experiments explore the role of bottlenecks in selective attention and access to visual short-term memory (VSTM) in the failure of observers to identify clearly visible changes in otherwise stable visual displays. Experiment 1 shows that observers fail to register a colour change in an object even if they are cued to the location of the object by a transient at that location as the change is occurring. Experiment 2 shows the same for orientation change. In Experiments 3 and 4, attention is directed to specific objects prior to making changes in those objects. Observers have only a very limited memory for the status of recently attended items. Experiment 5 reveals that observers have no ability to detect changes that happen after attention has been directed to an object and before attention returns to that object. In Experiment 6, attention is cued at rates that more closely resemble natural rates and Experiment 7 uses natural images. Memory capacity remains very small (< 4 items). © 2006 Psychology Press Ltd.

Antidepressants affect memory and neural responses to emotionally valenced stimuli in healthy volunteers. However, it is unclear whether this extends to autobiographical memory for personally experienced events. The current study investigated the effects of acute administration of the antidepressant reboxetine on emotional autobiographical retrieval in healthy volunteers (14 men, 10 women). Functional magnetic resonance imaging was used in a double-blind between-groups investigation with reboxetine (4 mg) and placebo. Consistent with previous reports using lab-based stimuli, neural activation in the processing of positive versus negative memories was reduced following reboxetine compared with placebo in the left frontal lobe (extending into the insula) and the right superior temporal gyrus. This was paired with increased memory speed in volunteers given reboxetine versus placebo. The effect of reboxetine on emotional memory extends to recall of personally experienced events. Such effects may be relevant to the cognitive improvements found with recovery from depression and with the mechanism of action of contemporary antidepressant drugs.

The special status of spiders in the attentional bottleneck and visual working memory (VWM) was studied. 23 spider-fearfuls (SF) and 23 non-anxious controls (NACs) participated in a serial VWM-task. Each trial showed a 4 x 4 matrix of images and 5 of these were subsequently cued for 150 ms each. Afterwards, one of the 16 displayed images was hidden and probed. The spider image was included in the string of 5 cued images, among the 11 uncued items, or not at all. For both groups, memory was better for cued spiders than for other cued items. SFs also showed improved memory for uncued spiders. The relevance of the results for theories of attention and cognitive models of phobias are discussed.

Depressed mood is associated with making negatively biased interpretations of ambiguous everyday events. Experimental modification towards a more optimistic interpretation has become a focus of recent research. However, to date, no measures exist that have been tested with respect to their psychometric properties that justify repeated administration to capture change. We aimed to develop and evaluate a pragmatic assessment instrument, consisting of a 30-item questionnaire (long version) and two 15-item parallel short versions (A and B). Items were generated as ambiguous sentences, reflecting three relevant content areas based on Beck's cognitive triad. The sentences were rated for pleasantness, and this emotional appraisal task indicates the emotional valence of the interpretation. Due to the intention to develop a parallel test version, item-twins were generated. All three versions of the instrument were found to be structurally stable, internally consistent and valid. In line with Beck's cognitive triad in depression, confirmatory factor analyses determined a three-factor solution (i.e. self, experiences and future). Significant correlations were found between all scales and depressive mood. The two short versions represent the same underlying constructs, share identical psychometric properties and possess high parallel-test reliability. This study is the first to evaluate and confirm the factorial validity as well as the parallel-test reliability of an interpretation bias measure. It is suitable to measure bias modification and has therefore great potential for research and clinical practice. © 2014 Swedish Association for Behaviour Therapy.

Contains fulltext : 90449.pdf (Publisher’s version ) (Closed access) Following cognitive models of anxiety, biases occur if threat processing is automatic versus strategic. Therefore, most of these models predict attentional bias, but not explicit memory bias. We suggest dividing memory into the highly automatic working memory (WM) component versus long-term memory when investigating bias in anxiety. WM for threat has rarely been investigated although its main function is stimulus monitoring, particularly important in anxiety. We investigated WM for spiders in spider fearfuls (SFs) versus non-anxious controls (NACs). In Experiment 1 (23 SFs/24 NACs), we replicated an earlier WM study, reducing strategic processing options. This led to stronger group differences and, thus, clearer WM threat biases. There were no group differences in Experiment 2 (18 SFs/19 NACs), using snakes instead of spiders to test whether WM biases are material-specific. This article supports cognitive models of anxiety in that biases are more likely to occur when reducing strategic processing. However, it contradicts the assumption that explicit memory biases are not characteristic of anxiety.

The role of attentional biases in panic disorder has been well characterised. However, recent studies suggest an important effect of antidepressant and anxiolytic drugs on cognitive bias and most studies have included medicated patients in their sample. This study therefore examined cognitive bias in an untreated sample of participants with panic disorder (PD). A sample of 23 untreated participants with panic disorder with or without agoraphobia (PPD) and 22 healthy controls (HC) were tested with a Facial Expression Recognition task featuring different emotional intensities, a Faces Dot Probe task, a Self Beliefs task and an Emotional Stroop task. PPD showed exaggerated attentional biases to negative face and word stimuli in two different paradigms and endorsed more panic-related and negative self-attributions. They also showed enhanced perception of facial expressions of sadness. These tasks are sensitive to cognitive bias in a community-based sample of untreated PD participants. Attentional biases in panic disorder cannot be explained by the use of medication in this group and may therefore play a critical role in the underlying pathogenesis of the disorder.

This study investigated whether trauma-related stimuli are preferentially processed at the expense of ongoing processing of neutral stimuli. Participants in the experimental group viewed negative pictures (Trauma) as an analogue trauma induction. Participants in the control group viewed visually similar neutral pictures (Neutral Match). In a Rapid Serial Visual Presentation (RSVP) task participants identified two target pictures. The first target (T1) was a neutral picture, whereas the second target (T2) was a familiar negative or neutral picture or a new neutral or negative picture. In line with hypotheses, only participants in the experimental group showed preferential processing of Trauma pictures. In the experimental group, negative T2 impaired the identification of (neutral) T1 if the T2 immediately followed the T1 in the RSVP stream. The results are consistent with a processing priority of trauma-related information, apparently at the expense of the ongoing processing of neutral information. (C) 2012 Elsevier Ltd. All rights reserved.

Massed exposure has gained acceptance as an effective method to treat anxiety disorders. When using this intervention in patients presenting with more than one anxiety disorder, specific treatment options need to be discussed. Should exposure be applied in sequential order for each of the comorbid disorders? Or can exposure sessions also be designed to simultaneously target both problem areas? We report on the cognitive-behavioral treatment of a 28-year-old woman with obsessive-compulsive disorder (OCD) and severe panic disorder with agoraphobia (PDA). A series of behavioral experiments based on prolonged exposure was planned. Due to the fact that avoided situations elicited both agoraphobic and contamination fears, we decided to combine exposure for PDA and OCD to optimize therapeutic transfer. Twelve sessions of this exposure resulted in a long-term reduction of both PDA and OCD symptoms. The case illustrates that two comorbid conditions can be effectively combined under one therapeutic rationale. Capabilities and limitations of the method and implications for current theoretical debates on exposure therapy are discussed.

Contains fulltext : 90564.pdf (Publisher’s version ) (Closed access) Anxiety disorders are characterized by biased implicit threat associations, which can be measured by indirect reaction time tasks. These tasks might provide a useful tool in the assessment of individual diagnoses and therapeutic changes. However, sufficient psychometric properties of the applied tasks are a prerequisite for these applications. Therefore, we comparatively investigated the reliability and validity of an Extrinsic Affective Simon Task (EAST), an Approach-Avoidance Task (AAT), and an Affective Priming Task (APT) by presenting the same tasks twice within 1 week. Data show retest reliabilities of around r = .42 for the EAST, r = .35 for the AAT, and r = .63 for the APT. Internal consistencies varied between .44 and .49 for the EAST, .66 and .70 for the AAT, and .53 and .76 for the APT. Validity correlations with self-report questionnaires ranged between r = .43 and r = .59, being lowest for the EAST and highest for the AAT. We argue that while these instruments might not be applicable to individual diagnostics yet, they are sufficiently reliable and valid to be used in the assessment of group differences.

Background and objectives One of the central assumptions of cognitive models of Panic Disorder (PD) is that automatic panic-related associations are a core feature of PD. However, empirical findings are mixed and inconsistent, rendering it difficult to evaluate the role of panic-related associations adequately, particularly in relation to the relevant theories. The present study aimed to further advance our understanding of automatic associations in PD, and therefore applied a paradigm novel in this context, namely an Extrinsic Affective Simon Task (EAST). Methods Participants involved treatment seeking, unmedicated panic patients (n = 45) and healthy controls (n = 38). The EAST was applied prior to treatment. It included the following stimuli as targets: panic-related bodily sensations and agoraphobia-related situations, and as attributes: pleasant versus unpleasant, fear-related words. Results Contrary to our expectations, panic patients did not show stronger negative than positive automatic associations for either panic-related symptoms or agoraphobia-related situations, compared to healthy controls. Moreover, EAST effects did not correlate with panic-related self-report measures. Limitations Although the present study involved patients who were actively seeking treatment, panic-related associations might not have been activated sufficiently. Hence, a brief activation procedure (e.g., hyperventilation) might have been needed to optimize the assessment condition. Conclusions The present findings do not support contemporary theories of panic-related associations. Therefore, follow-up work is needed to disentangle their functional and operational properties more thoroughly., Highlights • Automatic panic-related associations are a core feature of Panic Disorder. • We assessed them by means of an Extrinsic Affective Simon Task (EAST). • We tested panic patients (PP) and healthy controls (HC). • PP did not show stronger negative automatic panic-related associations than HC.

Highlights • The first cue-based task to explore recall of dyspnoea and dyspnoea-related anxiety in COPD. • Patients’ dyspnoea and dyspnoea-anxiety ratings agreed with established measures of dyspnoea. • Patients’ dyspnea-anxiety ratings changed in accordance with clinical improvement. • The task was reliable and well tolerated. • The task is suitable for FMRI use and may aid dyspnoea neuroimaging research., Patients with chronic dyspnoea may learn to fear situations that cue dyspnoea onset. Such dyspnoea-specific cues may then cause anxiety, and worsen or trigger dyspnoea even before commencement of physical activity. We therefore developed an experimental tool to probe emotional processing of dyspnoea for use with neuroimaging in COPD. The tool consists of a computerised task comprising multiple presentations of dyspnoea-related word cues with subsequent rating of dyspnoea and dyspnoea-anxiety with a visual analogue scale. Following 3 development stages, sensitivity to clinical change was tested in 34 COPD patients undergoing pulmonary rehabilitation. We measured internal consistency, sensitivity to clinical change and convergence with established dyspnoea measures (including Dyspnoea-12). Cronbach’s alpha was 0.90 for dyspnoea and 0.94 for dyspnea-anxiety ratings. Ratings correlated with Dyspnoea-12 (dyspnoea: r = 0.51, P = 0.002; dyspnea-anxiety: r = 0.54, P = 0.001). Reductions in dyspnea-anxiety ratings following pulmonary rehabilitation correlated with reductions in Dyspnoea-12 (r = 0.51, P = 0.002). We conclude that the word-cue task is reliable, and is thus a potentially useful tool for neuroimaging dyspnoea research.

Neuroimaging studies in anorexia nervosa (AN) suggest that altered food reward processing may result from dysfunction in both limbic reward and cortical control centers of the brain. This fMRI study aimed to index the neural correlates of food reward in a subsample of individuals with restrictive AN: twelve currently ill, fourteen recovered individuals and sixteen healthy controls. Participants were shown pictures of high and low-calorie foods and asked to evaluate how much they wanted to eat each one following a four hour fast. Whole-brain task-activated analysis was followed by psychophysiological interaction analysis (PPI) of the amygdala and caudate. In the AN group, we observed a differential pattern of activation in the lateral frontal pole: increasing following presentation of high-calorie stimuli and decreasing in during presentation of low-calorie food pictures, the opposite of which was seen in the healthy control (HC) group. In addition, decreased activation to food pictures was observed in somatosensory regions in the AN group. PPI analyses suggested hypo-connectivity in reward pathways, and between the caudate and both somatosensory and visual processing regions in the AN group. No significant between-group differences were observed between the recovered group and the currently ill and healthy controls in the PPI analysis. Taken together, these findings further our understanding of the neural processes which may underpin the avoidance of high-calorie foods in those with AN and might exacerbate the development of compulsive weight-loss behavior, despite emaciation., Highlights • We compared neural responses to high vs low calorie food pictures in restrictive AN. • We used both fMRI whole brain and PPI analyses. • Frontal pole hyper-activated by high calorie foods in AN, the opposite to controls. • Reduced functional connectivity in reward patthways and somatosensory regions in AN.

This review highlights established and more recently recognized risk factors for coronary heart disease (CHD) relevant for patients seen in primary care, emphasizing the key role of diabetes mellitus type 2. Recent trends in risk factor research as well as current methods of risk stratification, and new systemic markers are discussed. Beyond the need for more forceful public health strategies to improve early recognition and intervention, the necessity of an integrated comprehensive investigation of the overall characteristics of cardiovascular disease, especially in primary care patients as a prerequisite for future concerted actions is pointed out. Based on this, a large-scale epidemiological investigation focusing on CHD and diabetes in the primary care sector is suggested.

N-methyl-D-aspartate (NMDA) receptors are known to fulfill crucial functions in many forms of learning and plasticity. More recently, biophysical models, however, have suggested an additional role of NMDA receptors in evidence integration for decision-making, going beyond their role in learning. We designed a task to study the role of NMDA receptors in human reward-guided learning and decision-making. Human participants were assigned to receive either 250 mg of the partial NMDA agonist d-cycloserine (n=20) or matching placebo capsules (n=27). Reward-guided learning and decision-making were assessed using a task in which participants had to integrate learnt and explicitly shown value information to maximize their monetary wins and minimize their losses. To tease apart the effects of NMDA on learning and decision-making we used simple learning models. D-cycloserine shifted decision-making towards a more optimal integration of the learnt and the explicitly shown information, in the absence of a direct learning effect. In conclusion, our results reveal a distinct role for NMDA receptors in reward-guided decision-making. We discuss these findings in the context of NMDA's roles in neuronal super-additivity and as crucial for evidence integration for decisions.

Although cognitive-behavioural therapy (CBT) is an effective first-line intervention for anxiety disorders, treatments remain long and cost-intensive, difficult to access, and a subgroup of patients fails to show any benefits at all. This study aimed to identify functional and structural brain markers that predict a rapid response to CBT. Such knowledge will be important to establish the mechanisms underlying successful treatment and to develop more effective, shorter interventions. Fourteen unmedicated patients with panic disorder underwent 3 T functional and structural magnetic resonance imaging (MRI) before receiving four sessions of exposure-based CBT. Symptom severity was measured before and after treatment. During functional MRI, patients performed an emotion regulation task, either viewing negative images naturally, or intentionally down-regulating negative affect by using previously taught strategies of cognitive reappraisal. Structural MRI images were analysed including left and right segmentation and volume estimation. Improved response to brief CBT was predicted by increased pre-treatment activation in bilateral insula and left dorsolateral prefrontal cortex (dlPFC) during threat processing, as well as increased right hippocampal gray matter volume. Previous work links these regions to improved threat processing and fear memory activation, suggesting that the activation of such mechanisms is crucial for exposure-based CBT to be effective.

Negative interpretation is thought to be crucial in the development and maintenance of depression. Recently developed cognitive bias modification paradigms, intending to change these biases towards a more optimistic interpretation tendency (CBM-I), seem to offer new promising implications for cognitive therapy innovation. This study aimed to increase our knowledge of the underlying mechanisms of action of imagery-based CBM-I in the context of depressed mood. We therefore compared the efficacy of CBM-I requiring participants to imagine standardized positive resolutions to a novel, more active training version that required participants to generate the positive interpretations themselves. Fifty-four participants were randomly allocated to (1) standardized CBM-I, (2) self-generation CBM-I or (3) a control group. Outcome measures included self-report mood measures and a depression-related interpretation bias measure. Both positive training variants significantly increased the tendency to interpret fresh ambiguous material in an optimistic manner. However, only the standardized imagery CBM-I paradigm positively influenced mood. © 2013 The Authors.