Miquel A. Fullana

Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies

Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the ‘central autonomic–interoceptive network’. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations—a scarcely addressed dynamic in fMRI fear-conditioning studies—also suggests the existence of a coordinated brain response potentially underlying the ‘safety signal’ (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches.

A Multivariate Twin Study of Obsessive-Compulsive Symptom Dimensions

CONTEXT Obsessive-compulsive disorder (OCD) is clinically heterogeneous, but it is unclear whether this phenotypic heterogeneity reflects distinct, or partially distinct, etiologic mechanisms. OBJECTIVE To clarify the structure of the genetic and environmental risk factors for the major symptom dimensions of OCD. DESIGN Self-report questionnaires and multivariate twin model fitting. SETTING General community. PARTICIPANTS A total of 4355 female members of the TwinsUK adult twin register. MAIN OUTCOME MEASURES Scores on the Obsessive-Compulsive Inventory-Revised and 5 of its subscales (checking, hoarding, obsessing, ordering, and washing). RESULTS A common pathway model did not fit the data well, indicating that no single latent factor can explain the heterogeneity of OCD. The best-fit multivariate twin model was an independent pathway model, whereby both common and unique genetic and/or environmental factors contribute to the etiology of each symptom dimension. The hoarding dimension had the lowest loading on the common factor and was more influenced by specific genetic effects (54.5% specific). With the exception of hoarding, most of the genetic variance was due to shared genetic factors (ranging from 62.5% to 100%), whereas most of the nonshared environmental variance was due to dimension-specific factors. CONCLUSIONS Obsessive-compulsive disorder is unlikely to be an etiologically homogeneous condition. There is substantial etiologic overlap across the different OC symptom dimensions, but dimension-specific genetic, and particularly nonshared environmental, factors are at least as important. Hoarding shares the least amount of genetic liability with the remaining symptom dimensions. The results have implications for the current deliberations regarding OCD and the inclusion of a putative hoarding disorder in DSM-5.

High sensitivity to punishment and low impulsivity in obsessive-compulsive patients with hoarding symptoms

Recent factor-analytic studies involving over 2000 patients have reduced the symptoms of obsessive-compulsive disorder (OCD) into a few dimensions or potentially overlapping syndromes. Hoarding consistently emerged as a separate factor in all these studies. This study investigated the relationship between OCD symptom dimensions and normal personality traits in a sample of 56 OCD patients. They were administered the Sensitivity to Punishment and Sensitivity to Reward Questionnaire and the Eysenck Personality Questionnaire, derived from Grays and Eysencks personality models, respectively. The personality scores were correlated with previously identified symptom dimensions from the Yale-Brown Obsessive-Compulsive Scale Symptom Checklist (Y-BOCS-SC), controlling for overall illness severity. High scores on the hoarding dimension of the Y-BOCS-SC were positively correlated with scores on the Sensitivity to Punishment scale and negatively with Eysencks Psychoticism scale. While high sensitivity to punishment is a personality feature common to many OCD patients, it is more strongly pronounced in patients with hoarding symptoms. These patients also appear to be less impulsive or novelty seeking as reflected by low scores on Eysencks Psychoticism scale. High sensitivity to punishment and low novelty seeking in OCD hoarders might explain their poor compliance and response to conventional treatments, but this question needs to be explored further in a prospective treatment study.

Joint hypermobility syndrome is a risk factor trait for anxiety disorders: a 15-year follow-up cohort study

OBJECTIVE The objective of the study was to assess whether joint hypermobility syndrome (JHS) is a risk factor for developing anxiety disorders using a 15-year prospective cohort study. METHOD The initial cohort recruited 158 subjects aged 16 to 20 years from the general population in a Spanish rural town. The cohort was studied at baseline and at a 15-year follow-up. Joint hypermobility syndrome was assessed using Beightons criteria, and the psychiatric disorders were assessed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Disorders. Subjects with anxiety disorders at baseline were excluded from the follow-up. RESULTS Joint hypermobility syndrome at baseline was found in 29 of 158 subjects (21.1%). Cumulative incidence of panic/agoraphobia disorder at follow-up, as main diagnosis, was significantly higher for the JHS group (41.4%) than for the control group (1.9%), with a relative risk of 22.3 [95% confidence interval (CI) 4.6-108.7, P<.0001] (Number Needed to Treat [NNT] 3, 95% CI 2.9-2.3). Incidence of social phobia and simple phobia was also significantly higher for the JHS group [relative risk (RR)=6.52, 95% CI 1.7-24.2, P<.001 and RR=3.31, 95% CI 1.1-9.6, P=.02, respectively]. Moreover, anxiolytic drug use was nearly fourfold higher among JHS compared to non-JHS subjects. CONCLUSION Joint hypermobility syndrome was associated with higher risk of developing anxiety disorders. If replicated, these findings may give enhanced value to JHS assessment in clinical and general population studies.

Personality characteristics in obsessive-compulsive disorder and individuals with subclinical obsessive-compulsive problems

OBJECTIVE To assess the relationship between normal personality traits and obsessive-compulsive (OC) phenomena in individuals with subclinical OC problems and patients whose problems met diagnostic criteria for obsessive-compulsive disorder (OCD). METHOD In Study 1, 25 healthy volunteers with high scores on the Padua Inventory (PI) and 28 controls with low scores on the PI were compared on the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ), the Eysenck Personality Questionnaire (EPQ), and measures of depression and state anxiety. In Study 2, 56 treatment-seeking participants meeting DSM-IV criteria for OCD and 40 healthy volunteers of similar sociodemographic characteristics were compared on the same measures. RESULTS Both individuals with subclinical OC problems and OCD patients scored significantly higher than their respective control groups on sensitivity to punishment, neuroticism and psychoticism. OCD patients, but not individuals with subclinical OC problems, scored lower in extraversion than their respective controls. Neuroticism was the strongest predictor of high scores on the PI in Study 1, while psychoticism was the strongest predictor of the presence of an OCD diagnosis in Study 2. CONCLUSION Healthy participants with high scores on OC measures and OCD patients share various personality traits but can also be distinguished according to the level of extraversion, neuroticism and psychoticism.

Convergent and discriminant validity of the Yale-Brown Obsessive-Compulsive Scale Symptom Checklist

Background: The factor structure of the Yale-Brown Obsessive-Compulsive Scale Symptom Checklist (Y-BOCS-SC) has been well established, but its convergent and divergent reliability have yet to be studied. Methods: Fifty-six obsessive-compulsive disorder (OCD) patients were administered the clinician-administered Y-BOCS-SC and Hamilton Rating Scale for Depression (HRSD), together with the self-administered Maudsley Obsessive Compulsive Inventory (MOCI), Padua Inventory (PI), State-Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI). Results: Overall, the correspondence between the Y-BOCS-SC and self-administered measures of OCD symptoms was poor to moderate. Its convergent validity was adequate for its washing dimension but poor for its other dimensions. The discriminant validity of the Y-BOCS-SC was adequate, showing little overlap with overall illness severity (total Y-BOCS) and state measures (BDI, STAI, HRSD). In contrast, self-administered OCD measures were significantly correlated with overall illness severity and state measures. Conclusions: The convergent validity of the Y-BOCS-SC was generally poor and this could only be partially explained by the incomplete coverage of some OCD symptoms in the self-administered scales. Its discriminant validity was good. Both self- and clinician-administered measures should be used in OCD research, as they seem to measure relatively non-overlapping constructs. Further research on the psychometric properties of the Y-BOCS-SC is needed.

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.

Predicting response to cognitive behavioral therapy in contamination-based obsessive-compulsive disorder from functional magnetic resonance imaging

BACKGROUND Although cognitive behavioral therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD), few reliable predictors of treatment outcome have been identified. The present study examined the neural correlates of symptom improvement with CBT among OCD patients with predominantly contamination obsessions and washing compulsions, the most common OCD symptom dimension. METHOD Participants consisted of 12 OCD patients who underwent symptom provocation with contamination-related images during functional magnetic resonance imaging (fMRI) scanning prior to 12 weeks of CBT. RESULTS Patterns of brain activity during symptom provocation were correlated with a decrease on the Yale-Brown Obsessive Compulsive Scale (YBOCS) after treatment, even when controlling for baseline scores on the YBOCS and the Beck Depression Inventory (BDI) and improvement on the BDI during treatment. Specifically, activation in brain regions involved in emotional processing, such as the anterior temporal pole and amygdala, was most strongly associated with better treatment response. By contrast, activity in areas involved in emotion regulation, such as the dorsolateral prefrontal cortex, correlated negatively with treatment response mainly in the later stages within each block of exposure during symptom provocation. CONCLUSIONS Successful recruitment of limbic regions during exposure to threat cues in patients with contamination-based OCD may facilitate a better response to CBT, whereas excessive activation of dorsolateral prefrontal regions involved in cognitive control may hinder response to treatment. The theoretical implications of the findings and their potential relevance to personalized care approaches are discussed.

Looking at the heart of low and high heart rate variability fearful flyers: self-reported anxiety when confronting feared stimuli.

Previous research has shown that phobic subjects with low heart rate variability (HRV) are less able to inhibit an inappropriate response when confronted with threatening words compared to phobic subjects with high HRV [Johnsen, B.H., Thayer, J.F., Laberg, J.C., Wormnes, B., Raadal, M., Skaret, E., et al., 2003. Attentional and physiological characteristics of patients with dental anxiety. Journal of Anxiety Disorders, 17, 75-87]. The aim of this study was to evaluate changes in self-reported anxiety when low HRV and high HRV fearful flyers (N=15) and a matched control group (N=15) were exposed to flight-related pictures, flight-related sounds or both pictures and sounds. We hypothesized that sounds would be crucial to evoke fear. Also, low HRV fearful flyers were expected to report higher anxiety than high HRV fearful flyers assuming anxiety as their inappropriate response. Decreases on HRV measures were also predicted for a subgroup of phobic participants (N=10) when confronted with the feared stimuli. Our data supported the hypothesis that sounds are crucial in this kind of phobia. Low HRV fearful flyers reported higher anxiety than high HRV fearful flyers in two out of three aversive conditions. The predicted HRV decreases were not found in this study. Results are discussed in the context of avoidance of exposure-based treatments.

Computer-Assisted Exposure Treatment for Flight Phobia: a Controlled Study

This study examines the efficacy of computer-assisted exposure (CAE) treatment in helping to overcome flight phobia and analyzes the role of relaxation and information-related components in the reduction of fear. Fifty flight phobics were randomly assigned to 1 of 3 methods of treatment: (a) CAE; (b) a multicomponent method of treatment of information, relaxation, and CAE (IRCAE); and (c) waiting list control treatment. At the end of the treatment, an actual flight was chartered. The results showed that the first 2 methods of treatments were more effective than the waiting list control treatment. The CAE group showed the greatest reduction in fear. According to data from the IRCAE group, no reduction in flight phobia was observed after the information-relaxation phase. Follow-up data showed that improvements in anxiety self-assessment rates remained constant.