Evidence for distinct genetic and environmental influences on fear acquisition and extinction.

BACKGROUND: Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction. METHODS: In total, 1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase. RESULTS: Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4-0.5). CONCLUSIONS: Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

Validating the use of a smartphone app for remote administration of a fear conditioning paradigm.

Fear conditioning models key processes related to the development, maintenance and treatment of anxiety disorders and is associated with group differences in anxiety. However, laboratory administration of tasks is time and cost intensive, precluding assessment in large samplesnecessary for the analysis of individual differences. This study introduces a newly developed smartphone app that delivers a fear conditioning paradigm remotely using a loud human scream as an aversive stimulus. Three groups of participants (total n = 152) took part in three studies involving a differential fear conditioning experiment to assess the reliability and validity of a smartphone administered fear conditioning paradigm. This comprised of fear acquisition, generalisation, extinction, and renewal phases during which online US-expectancy ratings were collected during every trial with evaluative ratings of negative affect at three time points. We show that smartphone app delivery of a fear conditioning paradigm results in a pattern of fear learning comparable to traditional laboratory delivery and is able to detect individual differences in performance that show comparable associations with anxiety to the prior group differences literature.

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Genome-wide expression and response to exposure-based psychological therapy for anxiety disorders.

Exposure-based psychological treatments for anxiety have high efficacy. However, a substantial proportion of patients do not respond to therapy. Research examining the potential biological underpinnings of therapy response is still in its infancy, and most studies have focussed on candidate genes. To our knowledge, this study represents the first investigation of genome-wide expression profiles with respect to treatment outcome. Participants (n=102) with panic disorder or specific phobia received exposure-based cognitive behavioural therapy. Treatment outcome was defined as percentage reduction from baseline in clinician-rated severity of their primary anxiety diagnosis at post treatment and 6 month follow-up. Gene expression was determined from whole blood samples at three time points using the Illumina HT-12v4 BeadChip microarray. Linear regression models tested the association between treatment outcome and changes in gene expression from pre-treatment to post treatment, and pre-treatment to follow-up. Network analysis was conducted using weighted gene co-expression network analysis, and change in the detected modules from pre-treatment to post treatment and follow-up was tested for association with treatment outcome. No changes in gene expression were significantly associated with treatment outcomes when correcting for multiple testing (q<0.05), although a small number of genes showed a suggestive association with treatment outcome (q<0.5, n=20). Network analysis showed no association between treatment outcome and change in gene expression for any module. We report suggestive evidence for the role of a small number of genes in treatment outcome. Although preliminary, these findings contribute to a growing body of research suggesting that response to psychological therapies may be associated with changes at a biological level.

Paediatric Obsessive-Compulsive Disorder and Depressive Symptoms: Clinical Correlates and CBT Treatment Outcomes.

Depression frequently co-occurs with paediatric obsessive-compulsive disorder (OCD), yet the clinical correlates and impact of depression on CBT outcomes remain unclear. The prevalence and clinical correlates of depression were examined in a paediatric specialist OCD-clinic sample (N = 295; Mean = 15 [7 - 18] years, 42 % female), using both dimensional (Beck Depression Inventory-youth; n = 261) and diagnostic (Development and Wellbeing Assessment; n = 127) measures of depression. The impact of depressive symptoms and suspected disorders on post-treatment OCD severity was examined in a sub-sample who received CBT, with or without SSRI medication (N = 100). Fifty-one per-cent of patients reported moderately or extremely elevated depressive symptoms and 26 % (95 % CI: 18 - 34) met criteria for a suspected depressive disorder. Depressive symptoms and depressive disorders were associated with worse OCD symptom severity and global functioning prior to CBT. Individuals with depression were more likely to be female, have had a psychiatric inpatient admission and less likely to be attending school (ps < 0.01). OCD and depressive symptom severity significantly decreased after CBT. Depressive symptoms and depressive disorders predicted worse post-treatment OCD severity (ßs = 0.19 and 0.26, ps < 0.05) but became non-significant when controlling for pre-treatment OCD severity (ßs = 0.05 and 0.13, ns). Depression is common in paediatric OCD and is associated with more severe OCD and poorer functioning. However, depression severity decreases over the course of CBT for OCD and is not independently associated with worse outcomes, supporting the recommendation for treatment as usual in the presence of depressive symptoms.

Serotonin transporter [corrected] methylation and response to cognitive behaviour therapy in children with anxiety disorders.

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35-45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT.

Psychometric properties of reaction time based experimental paradigms measuring anxiety-related information-processing biases in children.

Theoretical frameworks highlight the importance of threat-related information-processing biases for understanding the emergence of anxiety in childhood. The psychometric properties of several tasks measuring these biases and their associations with anxiety were examined in an unselected sample of 9-year-old children (N=155). In each task, threat bias was assessed using bias scores reflecting task performance on threat versus non-threat conditions. Reliability was assessed using split-half and test-retest correlations of mean reaction times (RTs), accuracy and bias indices. Convergence between measures was also examined. Mean RTs showed substantial split-half and test-retest correlations. Bias score reliability coefficients were near zero and non-significant, suggesting poor reliability in children of this age. Additionally, associations between bias scores and anxiety were weak and inconsistent and performance between tasks showed little convergence. Bias scores from RT based paradigms in the current study lacked adequate psychometric properties for measuring individual differences in anxiety-related information-processing in children.

Neurotrophic gene polymorphisms and response to psychological therapy.

Therapygenetics, the study of genetic determinants of response to psychological therapies, is in its infancy. Here, we investigate whether single-nucleotide polymorphisms in nerve growth factor (NGF) (rs6330) and brain-derived neutrotrophic factor (BDNF) (rs6265) genes predict the response to cognitive behaviour therapy (CBT). Neurotrophic genes represent plausible candidate genes: they are implicated in synaptic plasticity, response to stress, and are widely expressed in brain areas involved in mood and cognition. Allelic variation at both loci has shown associations with anxiety-related phenotypes. A sample of 374 anxiety-disordered children with white European ancestry was recruited from clinics in Reading, UK, and in Sydney, Australia. Participants received manualised CBT treatment and DNA was collected from buccal cells using cheek swabs. Treatment response was assessed at post-treatment and follow-up time points. We report first evidence that children with one or more copies of the T allele of NGF rs6330 were significantly more likely to be free of their primary anxiety diagnosis at follow-up (OR = 0.60 (0.42-0.85), P = 0.005). These effects remained even when other clinically relevant covariates were accounted for (OR = 0.62 (0.41-0.92), P = 0.019). No significant associations were observed between BDNF rs6265 and response to psychological therapy. These findings demonstrate that knowledge of genetic markers has the potential to inform clinical treatment decisions for psychotherapeutic interventions.

Experimental modification of interpretation bias regarding social and animal fear in children.

Using an experimental bias modification task, an interpretation bias towards or away from threat was induced about animal or social situations in a sample of 103 children split into a young (7-10 years) and old age group (11-15 years). Children rapidly learned to select outcomes of ambiguous situations which were congruent with their assigned modification condition. Following positive modification, children's threat interpretation biases significantly decreased, while threat biases increased (non-significantly) after negative modification. Bias modification effects also varied as a function of age with children appearing particularly vulnerable to acquiring biases about stimuli that were congruent with the normative fears for their age group. Weak age-related modification-congruent effects on younger but not older children's anxiety vulnerability in response to a behavioral task were also observed. However, no consistent effects of bias modification on avoidance behavior were found.

A funding model for a psychological service to plastic and reconstructive surgery in UK practice.

Appearance related distress in both clinical and general populations is associated with the increasing identification of surgery as a solution, leading to referrals for cosmetic surgery and pressure on NHS resources. Cosmetic surgery guidelines are designed to control this growing demand, but lack a sound evidence base. Where exceptions are provided on the basis of psychological need, this may recruit patients inappropriately into a surgical pathway, and creates a demand for psychological assessment which transfers the resource problem from one service to another. The model described below evaluates the impact of a designated psychology service to a plastic surgery unit. Developing an operational framework for delivering cosmetic guidelines, which assesses patients using clearly defined and measurable outcomes, has significantly reduced numbers of patients proceeding to the NHS waiting list and provided a systematic audit process. The associated cost savings have provided a way of funding a psychologist within the plastic surgery service so that psychological assessment becomes routine, alternative methods of treatment are easily available and all patients have access to psychological input as part of the routine standard of care.

Flawed gun policy research could endanger public safety.

A highly publicized recent study by Lott and Mustard concludes that laws easing restrictions on licenses for carrying concealed firearms in public substantially reduce violent crime. Several serious flaws in the study render the authors' conclusions insupportable. These flaws include misclassification of gun-carrying laws, endogeneity of predictor variables, omission of confounding variables, and failure to control for the cyclical nature of crime trends. Most of these problems should bias results toward overestimating the crime-reducing effects of laws making it easier to carry concealed firearms in public. Lott and Mustard's statistical models produce findings inconsistent with criminological theories and well-established facts about crime, and subsequent reanalysis of their data challenges their conclusions. Public health professionals should understand the methodological issues raised in this commentary, particularly when flawed research could influence the introduction of policies with potentially deleterious consequences.