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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.
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Encéfalo , Cicloserina , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Encéfalo/diagnóstico por imagen , Cicloserina/uso terapéutico , Diagnóstico por Imagen , Disnea/etiología , Disnea/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Calidad de Vida , Método Doble Ciego , RehabilitaciónRESUMEN
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.
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Disnea , Enfermedad Pulmonar Obstructiva Crónica , Afecto , Encéfalo/diagnóstico por imagen , Humanos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , SíndromeRESUMEN
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.
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Terapia Cognitivo-Conductual/métodos , Trastorno Depresivo Mayor/psicología , Trastorno Depresivo Mayor/terapia , Adulto , Reacción de Prevención , Conducta de Elección , Femenino , Humanos , Masculino , Persona de Mediana Edad , Listas de EsperaRESUMEN
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.
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Afecto , Depresión/psicología , Trastorno Depresivo/psicología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Psicológicos , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Adulto JovenRESUMEN
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.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II , Condicionamiento Clásico , Losartán , Losartán/farmacología , Losartán/administración & dosificación , Humanos , Masculino , Condicionamiento Clásico/efectos de los fármacos , Femenino , Método Doble Ciego , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Adulto , Adulto Joven , Reacción de Prevención/efectos de los fármacos , Presión Sanguínea/efectos de los fármacosRESUMEN
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.
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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.
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Condicionamiento Clásico , Aprendizaje Inverso , Humanos , Ansiedad , Miedo , Trastornos de AnsiedadRESUMEN
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.
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Research question: Pulmonary 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 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. Methods: 72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ClinicalTrials.gov identifier: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250â mg 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. An exploratory analysis determined the interaction with breathlessness anxiety. Results: No difference between d-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. Conclusion: 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.
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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.
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Trastorno por Déficit de Atención con Hiperactividad/etiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Sesgo , Trastorno de Pánico/complicaciones , Adulto , Atención/fisiología , Emoción Expresada/fisiología , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Trastorno de Pánico/psicología , Enmascaramiento Perceptual/fisiología , Estimulación Luminosa , Reconocimiento en Psicología/fisiología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
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.
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Terapia Cognitivo-Conductual/métodos , Hidrocortisona/farmacología , Terapia Implosiva/métodos , Trastornos Fóbicos/terapia , Adolescente , Adulto , Animales , Biomarcadores/metabolismo , Terapia Combinada , Método Doble Ciego , Femenino , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Glucocorticoides/farmacología , Humanos , Hidrocortisona/administración & dosificación , Masculino , Arañas , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
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Cicloserina/farmacología , Aprendizaje/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Adolescente , Adulto , Cognición/efectos de los fármacos , Método Doble Ciego , Agonismo Parcial de Drogas , Femenino , Humanos , Estudios Longitudinales , Masculino , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de Tiempo , Percepción del Tacto/efectos de los fármacos , Adulto JovenRESUMEN
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.
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Sesgo Atencional , Trastornos del Conocimiento , Cognición , Humanos , Aprendizaje Automático , Memoria a Corto Plazo , Metaanálisis como AsuntoRESUMEN
BACKGROUND: Cognitive schema theories of anxiety postulate that higher-level cognitive processes such as attention and memory are guided by underlying distorted fear associations. While numerous studies investigated these disorder-specific, biased processes, hardly any research addressed the underlying schemata themselves. In particular, no study has ever addressed implicit fear associations in Generalized Anxiety Disorder (GAD). In addition, no study has ever experimentally investigated the clinical observation that in GAD, patients' worry processes seem to be triggered by a broad range of materials, even by neutral or positive stimuli. METHODS: We used a Single Target Implicit Association Task (STIAT) to investigate implicit associations and stimulus generalization with clearly negative worry-related words (e.g., cancer, bankruptcy) and neutral words that are only indirectly related to worry topics (e.g., doctor, bank). Participants were 39 GAD patients and 23 healthy controls. RESULTS: In line with our expectations, both groups showed negative implicit associations with negative target words, and only GAD patients also associated neutral words with negative attributes. CONCLUSIONS: These results support the hypothesis that GAD patients' fear associations generalize to stimuli that are only peripherally related to the core of their worries.
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Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/psicología , Miedo , Trastornos de Ansiedad/epidemiología , Atención , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/epidemiología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Masculino , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/epidemiología , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , VocabularioRESUMEN
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).
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Cicloserina/uso terapéutico , Terapia Implosiva/métodos , Trastorno de Pánico/terapia , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/fisiopatología , Sesgo Atencional , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Agonismo Parcial de Drogas , Femenino , Neuroimagen Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Trastorno de Pánico/diagnóstico por imagen , Trastorno de Pánico/fisiopatología , Tiempo de Reacción , Receptores de N-Metil-D-Aspartato/agonistas , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
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.
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Cognición/efectos de los fármacos , Terapia Cognitivo-Conductual , Cicloserina/farmacología , Cicloserina/uso terapéutico , Miedo/efectos de los fármacos , Trastornos Fóbicos/psicología , Trastornos Fóbicos/terapia , Arañas , Adulto , Animales , Terapia Combinada , Femenino , Humanos , Masculino , Trastornos Fóbicos/tratamiento farmacológicoRESUMEN
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.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Angiotensinas/antagonistas & inhibidores , Cognición/efectos de los fármacos , Losartán/uso terapéutico , Estimulación Luminosa/efectos adversos , Trastornos por Estrés Postraumático/prevención & control , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Angiotensinas/fisiología , Cognición/fisiología , Método Doble Ciego , Femenino , Humanos , Losartán/farmacología , Masculino , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Trastornos por Estrés Postraumático/psicología , Adulto JovenRESUMEN
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.
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Amígdala del Cerebelo/fisiopatología , Expresión Facial , Miedo , Trastorno de Pánico/fisiopatología , Adulto , Femenino , Felicidad , Humanos , Imagen por Resonancia Magnética , Masculino , Trastorno de Pánico/psicologíaRESUMEN
BACKGROUND: 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 inhibitory learning whereby 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 may have similar synergistic effects on human exposure therapy, but the exact cognitive mechanisms underlying these effects remain unknown. METHODS: 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. In a double-blind parallel design, healthy volunteers were randomly assigned to single-dose losartan (50 mg) (n = 28) versus placebo (n = 25). Participants then performed a reinforcement learning task, which simultaneously probes appetitive and aversive learning. Participant choice behavior was analyzed using both a standard reinforcement learning model and analysis of choice switching behavior. RESULTS: 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 behavior. CONCLUSIONS: This study shows that 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.
Asunto(s)
Antagonistas de Receptores de Angiotensina/administración & dosificación , Conducta Apetitiva/efectos de los fármacos , Aprendizaje por Asociación/efectos de los fármacos , Miedo , Losartán/administración & dosificación , Adulto , Trastornos de Ansiedad/terapia , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Terapia Implosiva , Masculino , Castigo , Refuerzo en Psicología , Recompensa , Reino Unido , Adulto JovenRESUMEN
Temporal visual working memory (VWM) biases in spider anxiety were studied with an Attentional Blink paradigm. In Experiment 1, participants viewed pictures sequentially presented at rates of 80 ms and were instructed to memorize two target pictures. We varied time between targets and valence of the second target (neutral: mushroom, positive: blossom, negative: spider). In Experiment 2, spider fearfuls and non-anxious controls (both without snake anxiety) participated. Here we tested two negative targets: disorder-related spiders and disorder-irrelevant snakes. Both positive and negative items were memorized more successfully than neutral targets. Spiders were preferentially recalled by spider fearfuls compared to non-anxious controls, implying temporal VWM biases in spider anxiety. This advantage for threat was not related to a disruption of the encoding of non-threatening targets presented before the threat item.