Prediction error and overt attention to relevant and irrelevant cues: Evidence for an interaction of two associability mechanisms

Humans and other animals use cues in the environment to make predictions about important outcomes, thus preparing themselves to respond to those events. Prediction error refers to the extent to which an outcome is surprising in the presence of one or more cues. Within the research area of associative learning, some theories suggest that prediction error changes the amount of attention paid to cues. It was initially proposed that the attentional changes were driven by either relative or overall prediction error. In the first case, attention increases for cues generating less prediction error than other concurrent cues, otherwise attention decreases (Mackintosh, 1975). In the second case, the amount of attention paid to each cue is directly related to overall prediction error, i.e. how surprising the outcome is considering all the present cues (Pearce & Hall, 1980). Evidence for the role of relative prediction error comes from studies with pairs of cues including a component relevant to outcome prediction, together with an irrelevant component. Evidence for a role of overall prediction error comes from studies in which cues generating different amounts of prediction error are trained separately. Given that considering both relative and overall prediction error may account for a wider range of attentional changes, the two mechanisms were incorporated into hybrid models (e.g., Le Pelley, 2004). However, evidence for those models in humans is still scarce. The aim of the present thesis was to study the effect of a sudden rise in overall prediction error on overt attention to cues that were either relevant or irrelevant to outcome prediction, i.e. differing in terms of relative prediction error. Rather than considering sustained levels of prediction error, we focused primarily on sudden changes, because they are involved in important behavioral phenomena, such as the return of pathological anxiety. Each of the two studies included in the thesis started with a discrimination training, in which participants had to predict the occurrence of two possible outcomes. Participants’ eye gaze showed that the relevant cues received more attention than the irrelevant cues. In a second stage, contingency reversal (Study I) or partial reinforcement (Study II) led to a rise in prediction error, as indicated by a drop in the accuracy of outcome predictions. The attentional preference for the relevant cues was temporarily weakened by contingency reversal, and it was completely lost following the introduction of partial reinforcement. In addition, both manipulations increased the amount of attention paid to both types of cues. The data were consistent with a combined effect of relative and overall prediction error, thus providing evidence for the hybrid models. In addition, the results have implications for understanding changes in attention to contextual cues

Maximizar la terapia de exposición: Un enfoque basado en el aprendizaje inhibitorio

Despite the effectiveness of exposure therapy for treating anxiety disorders, a number of patients fail to benefit or experience a return of fear after treatment. Research suggests that anxious individuals show deficits in the mechanisms believed to underlie exposure therapy, such as inhibitory learning. Targeting these processes may help improve the efficacy of exposure-based procedures. The primary aim of this paper is to provide examples to clinicians of how to apply the inhibitory learning model in order to optimize exposure therapy.  Exposure optimization strategies include 1) expectancy violation, 2) deepened extinction, 3) occasional reinforced extinction, 4) removal of safety signals, 5) variability, 6) retrieval cues, 7) multiple contexts, and 8) affect labeling. Case studies illustrate methods of applying these techniques in a variety of anxiety disorders.A pesar de la efectividad de la terapia de exposición para el tratamiento de los trastornos de ansiedad, algunos pacientes no se benefician de ella o experimentan un retorno del miedo después del tratamiento. La investigación sugiere que las personas con ansiedad presentan déficits en los mecanismos supuestamente implicados en la terapia de exposición, como el aprendizaje inhibitorio. Centrarse en estos mecanismos podría mejorar la eficacia de los procedimientos basados en la exposición. El principal objetivo de este artículo es proporcionar ejemplos a los clínicos sobre cómo optimizar la terapia de exposición aplicando el modelo de aprendizaje inhibitorio. Las estrategias de optimización incluyen 1) violación de expectativas, 2) extinción intensificada, 3) refuerzo ocasional durante la extinción, 4) retirada de señales de seguridad, 5) variabilidad, 6) claves de recuperación, 7) contextos múltiples y 8) etiquetado de las emociones. Mediante estudios de caso se mostrarán formas de aplicar estas técnicas en varios trastornos de ansiedad

Hunger and Satiety Peptides: Is There a Pattern to Classify Patients with Prader-Willi Syndrome?

Hyperphagia is one of the main problems of patients with Prader-Willi syndrome (PWS) to cope with everyday life. The underlying mechanisms are not yet well understood. Gut-brain hormones are an interrelated network that may be at least partially involved. We aimed to study the hormonal profile of PWS patients in comparison with obese and healthy controls. Thirty adult PWS patients (15 men; age 27.5 ± 8.02 years; BMI 32.4 ± 8.14 kg/m2 ), 30 obese and 30 healthy controls were studied before and after eating a hypercaloric liquid diet. Plasma brain-derived neurotrophic factor (BDNF), leptin, total and active ghrelin, peptide YY (PYY), pancreatic polypeptide (PP), Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and amylin were determined at times 00 , 300 , 600 and 1200 . Cluster analysis was used. When considering all peptides together, two clusters were established according to fasting hormonal standardized concentrations. Cluster 1 encompassed most of obese (25/30) and healthy controls (28/30). By contrast, the majority of patients with PWS were located in Cluster 2 (23/27) and presented a similar fasting profile with hyperghrelinemia, high levels of leptin, PYY, GIP and GLP-1, compared to Cluster 1; that may reflect a dysfunction of these hunger/satiety hormones. When peptide behavior over the time was considered, PP concentrations were not sustained postprandially from 60 min onwards in Cluster 2. BDNF and amylin did not help to differentiate the two clusters. Thus, cluster analysis could be a good tool to distinguish and characterize the differences in hormone responses between PWS and obese or healthy controls

High Incidence of Copy Number Variants in Adults with Intellectual Disability and Co-morbid Psychiatric Disorders

Altres ajuts: Financial support was received from "Fundació Parc Taulí Institut d'Investigació i Innovació Parc Taulí I3PT" (Grant Nos. CIR2009/33, CIR2010/034) and "Fundació Barnola-Vallribera 2011".A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs-including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1-providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services

The impact of non-additive genetic associations on age-related complex diseases

Genome-wide association studies (GWAS) are not fully comprehensive, as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels and includes the analysis of the X chromosome and non-additive models to test for association. We apply this methodology to 62,281 subjects across 22 age-related diseases and identify 94 genome-wide associated loci, including 26 previously unreported. Moreover, we observe that 27.7% of the 94 loci are missed if we use standard imputation strategies with a single reference panel, such as HRC, and only test the additive model. Among the new findings, we identify three novel low-frequency recessive variants with odds ratios larger than 4, which need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases. Most genome-wide association studies assume an additive model, exclude the X chromosome, and use one reference panel. Here, the authors implement a strategy including non-additive models and find that the number of loci for age-related traits increases as compared to the additive model alone.Peer reviewe

Individual differences in the acquisition and generalization of fear: Testing the effects of the BDNF-val66met polymorphism and trait anxiety

La present tesi doctoral s’emmarca en el model d’ansietat patològica del condicionament de la por. D’acord amb aquest model, l’ansietat clínica prové de processos de condicionament de la por anòmals i altres factors de diàtesi-estrès relacionats. Aquesta idea ha rebut suport d’estudis que mostren condicionament anòmal de la por en individus diagnosticats amb trastorns d’ansietat, però les evidències sobre aquestes anomalies en individus en risc d’ansietat clínica són escasses. Per aquesta raó, examinàrem les diferencies individuals en l’adquisició i la generalització de la por condicionada en participants sans que es caracteritzaven per diferents nivells de susceptibilitat a l’ansietat patològica. Dues fonts de vulnerabilitat a l’ansietat varen ser investigades: la variació al·lèlica en el polimorfisme BDNF-val66met (estudi 1) i l’ansietat tret (estudi 2). Malgrat el gruix important de recerca que s’ha portat a terme recentment sobre la relació entre el polimorfisme BDNF-val66met i l’ansietat patològica, no està clar quin dels al·lels s’associa a un major risc als trastorns d’ansietat. Per tant, esperàvem que la variació en el polimorfisme BDNF-val66met es traduiria en diferències en l’adquisició i la generalització de la por, però no teníem cap hipòtesi sobre la direcció d’aquesta associació. Per altra banda, i donat que l’ansietat tret representa un factor de risc a l’ansietat patològica, esperàvem que els individus amb elevada ansietat tret mostrarien una adquisició anòmala de la por i excessiva generalització. A banda, i donades les implicacions a nivell teòric i metodològic, també estudiàrem l’estabilitat temporal de les diferències individuals en l’adquisició i generalització de la por (estudi enviat per a la seva publicació, inclòs a l’annex). En contra de les nostres prediccions, no trobàrem cap efecte del polimorfisme BDNF-val66met, o de l’ansietat tret, en l’adquisició i la generalització de la por. En les tres mesures de por (reflex d’ensurt, resposta de conductància de la pell, i expectatives online de l’estímul incondicionat aversiu), els participants de tots dos estudis van mostrar condicionament diferencial durant l’adquisició de la por i un gradient de generalització normal, caracteritzat per una disminució gradual de la por a mesura que els estímuls de generalització eren menys semblants al senyal de perill. Per altra banda, els resultats de l’estudi sobre l’estabilitat temporal de les diferències individuals en l’adquisició i la generalització de la por semblen indicar que una part moderada de la variabilitat en aquests processos és influïda per característiques individuals estables. D’acord amb els nostres resultats, concloguérem que el polimorfisme BDNF-val66met i l’ansietat tret no s’associen amb l’adquisició o generalització anòmales de la por condicionada. Per tant, més que una diàtesi preexistent a l’ansietat patològica, l’adquisició i generalització de la por anòmales podrien ser la conseqüència d’altres factors patogènics que condueixen a l’aparició de l’ansietat patològica.The present Ph D dissertation is framed within the fear-conditioning model of pathological anxiety. According to this model, clinical anxiety emerges from abnormal fear-conditioning processes and other related diathesis-stress factors. This has been supported by studies showing abnormal fear conditioning in individuals diagnosed with anxiety disorders, but evidence of these abnormalities in individuals at risk for clinical anxiety is rather scarce. Thus, we examined individual differences in the acquisition and generalization of conditioned fear in healthy participants characterized by different levels of susceptibility to pathological anxiety. Two sources of variability in vulnerability to anxiety were investigated: allele variation in the BDNF-val66met polymorphism (study 1) and trait anxiety (study 2). Despite the important body of research conducted recently on the relationship between the BDNF-val66met polymorphism and pathological anxiety, it is far from clear which of the polymorphism alleles is associated with increased risk for anxiety disorders. Thus, we expected that variation in BDNF-val66met polymorphism would lead to differences in the acquisition and generalization of fear, but we did not have any hypothesis about the direction of this association. On the other hand, and given that high trait anxiety represents an established risk factor for pathological anxiety, we expected that individuals with high trait anxiety would show abnormal fear acquisition and overgeneralization of fear. In addition, and given its important theoretical and methodological implications, we also tested the temporal stability of individual differences in the acquisition and generalization of conditioned fear (study submitted for publication included in the appendix). Contrary to our expectations, we did not find any effect of the BNDF-val66met polymorphism or trait anxiety on the acquisition and generalization of fear. For the three fear measures (startle reflex, skin conductance response, and online expectancies of the unconditioned aversive stimulus), participants from the two studies exhibited differential conditioning during fear acquisition and the normal generalization gradient, with a gradual decrease in fear as the generalization stimuli were less similar to the danger signal. On the other hand, the results of our unpublished study on the temporal stability of individual differences in the acquisition and generalization of fear suggest that a moderate part of the variability in these processes is influenced by stable individual characteristics. Based on our results, we concluded that the BDNF-val66met polymorphism or high trait anxiety is not associated with abnormal acquisition or generalization of conditioned fear. Thus, rather than a preexisting diathesis for pathological anxiety, abnormal acquisition and generalization of fear may be the result of other pathogenic factors that lead to the onset of an anxiety disorder

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ~100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.Peer Reviewe

Does fear extinction in the laboratory predict outcomes of exposure therapy? A treatment analog study

Fear extinction models have a key role in our understanding of anxiety disorders and their treatment with exposure therapy. Here, we tested whether individual differences in fear extinction learning and fear extinction recall in the laboratory were associated with the outcomes of an exposure therapy analog (ETA). Fifty adults with fear of spiders participated in a two-day fear-learning paradigm assessing fear extinction learning and fear extinction recall, and then underwent a brief ETA. Correlational analyses indicated that enhanced extinction learning was associated with better ETA outcome. Our results partially support the idea that individual differences in fear extinction learning may be associated with exposure therapy outcome, but suggest that further research in this area is needed.This work was supported by an ANPIR grant to E. F. (grant numberBA-3/2016); a KU Leuven program funding grant (grant number PF/10/005) and FP7 Marie Curie International Outgoing Fellowship (grantnumber 627743) to B. V.; PROMOSAM Investigación en procesos, me-canismos y tratamientos psicológicos para la promoción de la saludmental grant to M. T-F. (grant number PSI2014-56303-RED); Carlos IIIHealth Institute/FEDER grant to M. A. F. (grant number PI16/00144)

No effect of trait anxiety on differential fear conditioning or fear generalization

Previous studies have shown that individuals with anxiety disorders exhibit deficits in fear inhibition and excessive generalization of fear, but little data exist on individuals at risk from these disorders. The present study examined the role of trait anxiety in the acquisition and generalization of fear in 126 healthy participants selected on the basis of their trait-anxiety scores. Measures of conditioning included fear-potentiated startle, skin conductance response and online risk ratings for the unconditioned stimulus. Contrary to our hypotheses, trait anxiety did not have any effect either on the acquisition or the generalization of fear. Our results suggest that these fear conditioning processes are not impaired in individuals at risk from anxiety