The effect of prediction error on overt attention and learning in humans.

It has been suggested that attention modulates the speed at which cues come to predict contingent outcomes, and that attention changes with the prediction errors generated by cues. Evidence for this interaction in humans is inconsistent, with divergent findings depending on whether attention was measured with eye fixations or learning speed. We included both measures in our experiment. Initially, predictive cues (A and B) were consistently followed by one outcome (o1), while nonpredictive cues (X and Y) were followed by two randomly alternating outcomes (o1 and o2). Consistent with an effect of prediction error, participants' fixated for longer on the nonpredictive cues than on the predictive ones. Then, the cues were combined in three pairs: AX, followed by o1, and AY and BX, followed by o2. Discrimination of AX and AY depended on the previously nonpredictive cues and, given that these received more attention during initial training, it should proceed faster than discrimination of AX and BX, which depended on the previously predictive cues. However, participants learned to predict the outcomes of AY and BX at a similar rate. The fixation times were similar for the previously predictive and previously nonpredictive cues. We discuss reasons that could explain these findings.

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 0', 30', 60' and 120'. 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.

Neural correlates of fear conditioning and fear extinction and its association with cognitive-behavioral therapy outcome in adults with obsessive-compulsive disorder.

Recent neurobiological models of obsessive-compulsive disorder (OCD) have highlighted the potential role of abnormalities in fear learning processes. We compared brain activation -as assessed with whole-brain functional magnetic resonance imaging- during fear conditioning, fear extinction learning, and fear extinction recall in patients with OCD (n = 18) and healthy controls (n = 18). We also investigated whether brain activation during any of these processes was associated with exposure-based cognitive-behavioral therapy (CBT) outcome in patients. Patients with OCD showed significantly lower brain activation in the right insulo-opercular region and the dorsal anterior cingulate cortex during fear conditioning in comparison to healthy controls. Moreover, brain activation in the right insula predicted CBT outcome, with lower activation predicting a better outcome. Brain activation during extinction learning or recall did not differ between patients and controls or predicted CBT outcome in patients. Our results suggest that neural activations during fear conditioning in patients with OCD are abnormal and predict CBT outcome.

Evidence for two attentional mechanisms during learning.

We sought to provide evidence for a combined effect of two attentional mechanisms during associative learning. Participants' eye movements were recorded as they predicted the outcomes following different pairs of cues. Across the trials of an initial stage, a relevant cue in each pair was consistently followed by one of two outcomes, while an irrelevant cue was equally followed by either of them. Thus, the relevant cue should have been associated with small relative prediction errors, compared to the irrelevant cue. In a later stage, each pair came to be followed by one outcome on a random half of the trials and by the other outcome on the remaining half, and thus there should have been a rise in the overall prediction error. Consistent with an attentional mechanism based on relative prediction error, an attentional advantage for the relevant cue was evident in the first stage. However, in accordance with a mechanism linked to overall prediction error, the attention paid to both types of cues increased at the beginning of the second stage. These results showed up in both dwell times and within-trial patterns of fixations, and they were predicted by a hybrid model of attention.

Altered Gesture Imitation and Brain Anatomy in Adult Prader-Willi Syndrome Patients.

OBJECTIVE: To explore motor praxis in adults with Prader-Willi syndrome (PWS) in comparison with a control group of people with intellectual disability (ID) and to examine the relationship with brain structural measurements. METHOD: Thirty adult participants with PWS and 132 with ID of nongenetic etiology (matched by age, sex, and ID level) were assessed using a comprehensive evaluation of the praxis function, which included pantomime of tool use, imitation of meaningful and meaningless gestures, motor sequencing, and constructional praxis. RESULTS: Results support specific praxis difficulties in PWS, with worse performance in the imitation of motor actions and better performance in constructional praxis than ID peers. Compared with both control groups, PWS showed increased gray matter volume in sensorimotor and subcortical regions. However, we found no obvious association between these alterations and praxis performance. Instead, praxis scores correlated with regional volume measures in distributed apparently normal brain areas. CONCLUSIONS: Our findings are consistent in showing significant impairment in gesture imitation abilities in PWS and, otherwise, further indicate that the visuospatial praxis domain is relatively preserved. Praxis disability in PWS was not associated with a specific, focal alteration of brain anatomy. Altered imitation gestures could, therefore, be a consequence of widespread brain dysfunction. However, the specific contribution of key brain structures (e.g., areas containing mirror neurons) should be more finely tested in future research.

A rise in prediction error increases attention to irrelevant cues.

We investigated whether a sudden rise in prediction error widens an individual's focus of attention by increasing ocular fixations on cues that otherwise tend to be ignored. To this end, we used a discrimination learning task including cues that were either relevant or irrelevant for predicting the outcomes. Half of participants experienced contingency reversal once they had learned to predict the outcomes (reversal group, n = 30). The other half experienced the same contingencies throughout the task (control group, n = 30). As participants' prediction accuracy increased, they showed a decrease in the number of fixations directed to the irrelevant cues. Following contingency reversal, participants in the reversal group showed a drop in accuracy, indicating a rise in prediction error, and fixated on the irrelevant cues more often than participants in the control group. We discuss the results in the context of attentional theories of associative learning.

Compulsions in Prader-Willi syndrome: occurrence and severity as a function of genetic subtype.

INTRODUCTION: Compulsions are among the most typical behaviors in Prader-Willi syndrome (PWS). The most frequent causes of PWS are deletion of the genes located in the segment 15q11-q13 of the paternal allele and maternal uniparental disomy of cromosome 15. The aim of the present work was to study compulsive behavior in a sample of adults with PWS and analyze potential differences as a function of the genetic cause/subtype. MATERIAL AND METHODS: In the 27 study participants, existence of type I deletion (n=7), type II deletion (n=13), and maternal disomy (n=7) was determined by means of genetic tests. The Yale-Brown Obsessive Compulsive Scale, the Compulsive Behavior Checklist, and the Repetitive Behavior Questionnaire were used to assess occurrence and severity of compulsions. RESULTS: Most of the participants showed compulsive behavior, the most frequent compulsions were those of inappropriate grooming (skin picking) and order (hoarding). The occurrence of compulsions was less frequent in the maternal disomy group than in the deletion groups. Severe compulsions were more frequent in those participants with type II deletion than in the other groups. CONCLUSIONS: Differences in occurrence and severity of compulsions exist as a function of PWS genetic subtype. Our results support the idea that individuals with maternal disomy are less affected by compulsive behavior. More research on the severity of compulsions as a function of deletion type should be done, as the studies conducted so far have shown contradictory results.

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

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.

Translation and validation of the Spanish version of the Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD). / Traducción y validación de la versión española de la escala Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD).

INTRODUCTION: The Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD) is a brief instrument that assesses functioning in people with intellectual development disorder and mental health problems/behaviour disorders. The aim of the present study was to examine the evidence on the validity of the scores based on the Spanish version of the HoNOS-LD. MATERIAL AND METHODS: The study included 111 participants that were assessed by the Spanish version of the HoNOS-LD and other questionnaires that measured different variables related to the scale. Thirty-three participants were assessed by 2 examiners, and retested 7 days later, in order to study inter-examiner reliability and test-retest reliabilities. RESULTS: Based on clinical and conceptual criteria, and on the results of the parallel analysis, a factorial solution with one factor was selected. Internal consistency was good (Omega coefficient of 0.87). Inter-examiner and test-retest reliabilities were excellent (intraclass correlation coefficients of 0.95 and 0.98, respectively). Correlations between sections of the HoNOS-LD and the related instruments showed the expected direction, and were highly significant (P<.001), and the HoNOS-LD score increased with the intensity of the support required by the participants. These results showed evidence of the validity of association with other external variables. CONCLUSIONS: The Spanish version of the HoNOS-LD is a brief, valid and reliable instrument, which will enable a routine assessment of functioning for different uses, including diagnosis and intervention.

Attentional Control and Fear Extinction in Subclinical Fear: An Exploratory Study.

Attentional control (AC) and fear extinction learning are known to be involved in pathological anxiety. In this study we explored whether individual differences in non-emotional AC were associated with individual differences in the magnitude and gradient of fear extinction (learning and recall). In 50 individuals with fear of spiders, we collected measures of non-emotional AC by means of self-report and by assessing the functioning of the major attention networks (executive control, orienting, and alerting). The participants then underwent a paradigm assessing fear extinction learning and extinction recall. The two components of the orienting network functioning (costs and benefits) were significantly associated with fear extinction gradient over and above the effects of trait anxiety. Specifically, participants with enhanced orienting costs (i.e., difficulties in disengaging attention from cues not relevant for the task) showed faster extinction learning, while those with enhanced orienting benefits (i.e., attention facilitated by valid cues) exhibited faster extinction recall as measured by fear-potentiated startle and Unconditioned Stimulus expectancies, respectively. Our findings suggest that, in non-emotional conditions, the orienting component of attention may be predictive of fear extinction. They also show that the use of fear extinction gradients and the exploration of individual differences in non-emotional AC (using performance-based measures of attentional network functioning) can provide a better understanding of individual differences in fear learning. Our findings also may help to understand differences in exposure therapy outcomes.

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.

The Trail Making Test.

The Trail Making Test (TMT) is used as an indicator of visual scanning, graphomotor speed, and executive function. The aim of this study was to examine the TMT relationships with several neuropsychological measures and to provide normative data in community-dwelling participants of 55 years and older. A population-based Spanish-speaking sample of 2,564 participants was used. The TMT, Symbol Digit Test, Stroop Color-Word Test, Digit Span Test, Verbal Fluency tests, and the MacQuarrie Test for Mechanical Ability tapping subtest were administered. Exploratory factor analyses and regression lineal models were used. Normative data for the TMT scores were obtained. A total of 1,923 participants (76.3%) participated, 52.4% were women, and the mean age was 66.5 years (Digit Span = 8.0). The Symbol Digit Test, MacQuarrie Test for Mechanical Ability tapping subtest, Stroop Color-Word Test, and Digit Span Test scores were associated in the performance of most TMT scores, but the contribution of each measure was different depending on the TMT score. Normative tables according to significant factors such as age, education level, and sex were created. Measures of visual scanning, graphomotor speed, and visuomotor processing speed were more related to the performance of the TMT-A score, while working memory and inhibition control were mainly associated with the TMT-B and derived TMT scores.

Lack of Postprandial Peak in Brain-Derived Neurotrophic Factor in Adults with Prader-Willi Syndrome.

CONTEXT: Prader-Willi syndrome (PWS) is characterized by severe hyperphagia. Brain-derived neurotrophic factor (BDNF) and leptin are reciprocally involved in energy homeostasis. OBJECTIVES: To analyze the role of BDNF and leptin in satiety in genetic subtypes of PWS. DESIGN: Experimental study. SETTING: University hospital. SUBJECTS: 90 adults: 30 PWS patients; 30 age-sex-BMI-matched obese controls; and 30 age-sex-matched lean controls. INTERVENTIONS: Subjects ingested a liquid meal after fasting ≥10 hours. MAIN OUTCOME MEASURES: Leptin and BDNF levels in plasma extracted before ingestion and 30', 60', and 120' after ingestion. Hunger, measured on a 100-point visual analogue scale before ingestion and 60' and 120' after ingestion. RESULTS: Fasting BDNF levels were lower in PWS than in controls (p = 0.05). Postprandially, PWS patients showed only a truncated early peak in BDNF, and their BDNF levels at 60' and 120' were lower compared with lean controls (p<0.05). Leptin was higher in PWS patients than in controls at all time points (p<0.001). PWS patients were hungrier than controls before and after eating. The probability of being hungry was associated with baseline BDNF levels: every 50-unit increment in BDNF decreased the odds of being hungry by 22% (OR: 0.78, 95%CI: 0.65-0.94). In uniparental disomy, the odds of being hungry decreased by 66% (OR: 0.34, 90%CI: 0.13-0.9). Postprandial leptin patterns did no differ among genetic subtypes. CONCLUSIONS: Low baseline BDNF levels and lack of postprandial peak may contribute to persistent hunger after meals. Uniparental disomy is the genetic subtype of PWS least affected by these factors.

Conditioned Fear Acquisition and Generalization in Generalized Anxiety Disorder.

Abnormal fear conditioning processes (including fear acquisition and conditioned fear-generalization) have been implicated in the pathogenesis of anxiety disorders. Previous research has shown that individuals with panic disorder present enhanced conditioned fear-generalization in comparison to healthy controls. Enhanced conditioned fear-generalization could also characterize generalized anxiety disorder (GAD), but research so far is inconclusive. An important confounding factor in previous research is comorbidity. The present study examined conditioned fear-acquisition and fear-generalization in 28 patients with GAD and 30 healthy controls using a recently developed fear acquisition and generalization paradigm assessing fear-potentiated startle and online expectancies of the unconditioned stimulus. Analyses focused on GAD patients without comorbidity but included also patients with comorbid anxiety disorders. Patients and controls did not differ as regards fear acquisition. However, contrary to our hypothesis, both groups did not differ either in most indexes of conditioned fear-generalization. Moreover, dimensional measures of GAD symptoms were not correlated with conditioned fear-generalization indexes. Comorbidity did not have a significant impact on the results. Our data suggest that conditioned fear-generalization is not enhanced in GAD. Results are discussed with special attention to the possible effects of comorbidity on fear learning abnormalities.

Conditioned Subjective Responses to Socially Relevant Stimuli in Social Anxiety Disorder and Subclinical Social Anxiety.

UNLABELLED: Although enhanced fear conditioning has been implicated in the origins of social anxiety disorder (SAD), laboratory evidence in support of this association is limited. Using a paradigm employing socially relevant unconditioned stimuli, we conducted two separate studies to asses fear conditioning in individuals with SAD and non-clinical individuals with high social anxiety (subclinical social anxiety [SSA]). They were compared with age-matched and gender-matched individuals with another anxiety disorder (panic disorder with agoraphobia) and healthy controls (Study 1) and with individuals with low social anxiety (Study 2). Contrary to our expectations, in both studies, self-report measures (ratings of anxiety, unpleasantness and arousal to the conditioned stimuli) of fear conditioning failed to discriminate between SAD or SSA and the other participant groups. Our results suggest that enhanced fear conditioning does not play a major role in pathological social anxiety. KEY PRACTITIONER MESSAGE: We used a social conditioning paradigm to study fear conditioning in clinical and subclinical social anxiety. We found no evidence of enhanced fear conditioning in social anxiety individuals. Enhanced fear conditioning may not be a hallmark of pathological social anxiety.

Testing the temporal stability of individual differences in the acquisition and generalization of fear.

We studied the temporal stability of individual differences in the acquisition and generalization of fear. Seventy-one participants were tested in two almost identical fear-acquisition and fear-generalization sessions (separated by 8 months). Acquisition and generalization were measured by the fear-potentiated startle, the skin conductance response, and online expectancies of the unconditioned stimulus. To control for the effects of previous experience, different stimuli were used for half of the participants in Session 2. Acquisition and generalization did not differ across sessions or as a function of the stimuli used in Session 2, and a significant proportion of individual differences in these processes was stable over time (generalizability coefficients ranged from 0.17 to 0.38). When the same stimuli were used, acquisition measures showed compromised stability. The results are discussed in terms of their theoretical and applied implications.

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.

Acquisition and generalization of fear conditioning are not modulated by the BDNF-val66met polymorphism in humans.

Few studies have investigated the role of the BDNF-val66met polymorphism in fear conditioning in humans, and previous results have been inconsistent. In the present study, we examined whether the BDNF-val66met was associated with differences in the acquisition and generalization of fear during a differential conditioning paradigm in a large sample of participants (N = 141). Using three different indexes of fear learning (fear-potentiated startle, skin conductance response, and online risk ratings) no effects of the BDNF-val66met were found either on the acquisition or the generalization of conditioned fear. Taken together with previous data, our study suggests that the BDNF-val66met polymorphism has no effect on the acquisition or generalization of fear.

Impact when receiving a diagnosis: additive and multiplicative effects between illness severity and perception of control.

Based on Lazarus' transactional model of stress, this study examined how the information provided in a medical diagnosis (the severity of the illness, the effectiveness of the treatment and the self-efficacy to follow this treatment) are combined to generate perception of stress. Twenty-seven scenarios were presented to 152 volunteer students and their level of perceived stress was recorded. Results revealed that the lack of efficacy of the treatment raises the perception of stress proportionally to the different degrees of illness severity, but having a low perceived ability to follow the treatment triggers high levels of stress, particularly when the diagnosis is serious.