Subcortical brain volumes, cortical thickness and cortical surface area in families genetically enriched for social anxiety disorder - a multiplex multigenerational neuroimaging study

Background Social anxiety disorder (SAD) is a disabling psychiatric condition with a genetic background. Brain alterations in gray matter (GM) related to SAD have been previously reported, but it remains to be elucidated whether GM measures are candidate endophenotypes of SAD. Endophenotypes are measurable characteristics on the causal pathway from genotype to phenotype, providing insight in genetically-based disease mechanisms. Based on a review of existing evidence, we examined whether GM characteristics meet two endophenotype criteria, using data from a unique sample of SAD-patients and their family-members of two generations. First, we investigated whether GM characteristics co-segregate with social anxiety within families genetically enriched for SAD. Secondly, heritability of the GM characteristics was estimated. Methods Families with a genetic predisposition for SAD participated in the Leiden Family Lab study on SAD; T1-weighted MRI brain scans were acquired (n = 110, 8 families). Subcortical volumes, cortical thickness and cortical surface area were determined for a-priori determined regions of interest (ROIs). Next, associations with social anxiety and heritabilities were estimated. Findings Several subcortical and cortical GM characteristics, derived from frontal, parietal and temporal ROIs, co-segregated with social anxiety within families (uncorrected p-level) and showed moderate to high heritability. Interpretation These findings provide preliminary evidence that GM characteristics of multiple ROIs, which are distributed over the brain, are candidate endophenotypes of SAD. Thereby, they shed light on the genetic vulnerability for SAD. Future research is needed to confirm these results and to link them to functional brain alterations and to genetic variations underlying these GM changes

The Relation Between Cognitive Development and Anxiety Phenomena in Children

We examined the relation between cognitive development and fear, anxiety, and behavioral inhibition in a non-clinical sample of 226 Dutch children aged 4–9 years. To assess cognitive development, children were tested with Piagetian conservation tasks and a Theory-of-Mind (TOM) test. Fears were measured by means of a self-report scale completed by the children, while anxiety symptoms and behavioral inhibition were indexed by rating scales that were filled out by parents. Significant age trends were observed for some anxiety phenomena. For example, younger children displayed higher fear scores, whereas older children exhibited higher levels of generalized anxiety. Most importantly, results of regression analyses (in which we controlled for age) indicated that cognitive development, and in particular TOM ability, made a unique and significant contribution to various domains of behavioral inhibition. In all cases, higher levels of TOM were associated with lower levels of behavioral inhibition. In general, percentages of explained variance were rather small (i.e., <6%), indicating that the role of cognitive development in various anxiety phenomena is limited

Peer Perceptions of Social Skills in Socially Anxious and Nonanxious Adolescents

Previous studies using adult observers are inconsistent with regard to social skills deficits in nonclinical socially anxious youth. The present study investigated whether same age peers perceive a lack of social skills in the socially anxious. Twenty high and 20 low socially anxious adolescents (13–17 years old) were recorded giving a 5-min speech. Unfamiliar peer observers (12–17 years old) viewed the speech samples and rated four social skills: speech content, facial expressions, posture and body movement, and way of speaking. Peer observers perceived high socially anxious adolescents as significantly poorer than low socially anxious adolescents on all four social skills. Moreover, for all skills except facial expressions, group differences could not be attributed to adolescents’ self-reported level of depression. We suggest that therapists take the perceptions of same age peers into account when assessing the social skills of socially anxious youth

Distorted Cognitive Processing in Youth: The Structure of Negative Cognitive Errors and Their Associations with Anxiety

The Children’s Negative Cognitive Error Questionnaire (CNCEQ) is commonly used to measure four errors in young people’s thinking, but research has failed to support the factorial validity of the measure. The primary objective of the present study was to examine the factor structure of a refined and extended version of the CNCEQ. Revision of the CNCEQ involved the exclusion of items rated as contaminated, and the addition of items measuring cognitive errors closely associated with anxiety (‘threat conclusion’ and ‘underestimation of the ability to cope’). A secondary objective was to determine the relation between the negative cognitive errors and anxiety. Principal component analysis of data from 481 children and adolescents indicated five distinct negative cognitive error subscales labeled ‘underestimation of the ability to cope’, ‘personalizing without mind reading’, ‘selective abstraction’, ‘overgeneralizing’, and ‘mind reading’ which contained the new ‘threat conclusion’ items. Confirmatory factor analysis in an independent sample of 295 children and adolescents yielded further support for the five-factor solution. All cognitive errors except ‘selective abstraction’ were correlated with anxiety. Multiple regression analysis indicated that the strongest predictors of anxiety were the two subscales containing new items, namely ‘underestimation of the ability to cope’ and ‘mind reading’. The results are discussed with respect to further development of the instrument so as to advance the assessment of distorted cognitive processing in young people with internalizing symptoms

Cognitive Behavior Therapy for Anxious Adolescents: Developmental Influences on Treatment Design and Delivery

Anxiety disorders in adolescence are common and disruptive, pointing to a need for effective treatments for this age group. Cognitive behavior therapy (CBT) is one of the most popular interventions for adolescent anxiety, and there is empirical support for its application. However, a significant proportion of adolescent clients continue to report anxiety symptoms post-treatment. This paper underscores the need to attend to the unique developmental characteristics of the adolescent period when designing and delivering treatment, in an effort to enhance treatment effectiveness. Informed by the literature from developmental psychology, developmental psychopathology, and clinical child and adolescent psychology, we review the ‘why’ and the ‘how’ of developmentally appropriate CBT for anxious adolescents. ‘Why’ it is important to consider developmental factors in designing and delivering CBT for anxious adolescents is addressed by examining the age-related findings of treatment outcome studies and exploring the influence of developmental factors, including cognitive capacities, on engagement in CBT. ‘How’ clinicians can developmentally tailor CBT for anxious adolescents in six key domains of treatment design and delivery is illustrated with suggestions drawn from both clinically and research-oriented literature. Finally, recommendations are made for research into developmentally appropriate CBT for anxious adolescents

Modifying Threat-related Interpretive Bias in Adolescents

Socially anxious feelings sharply increase during adolescence and such feelings have been associated with interpretive biases. Studies in adults have shown that interpretive biases can be modified using Cognitive Bias Modification procedures (CBM-I) and subsequent effects on anxiety have been observed. The current study was designed to examine whether the CBM-I procedure has similar effects in adolescents. Unselected adolescents were randomly allocated to either a positive interpretation training (n = 88) or a placebo-control condition (n = 82). Results revealed that the training was successful in modifying interpretations and effects generalized to a new task. The interpretive bias effects were most pronounced in individuals with a threat-related interpretive bias at pre-test. No effects on state anxiety were observed. The current findings are promising with regard to applying bias modification procedures to adolescents, while further research is warranted regarding emotional effects

Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans

DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 � 10?6). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability

A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice

Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway

The direction of effects between perceived parental behavioral control and psychological control and adolescents’ self-reported GAD and SAD symptoms

This study examined the direction of effects and age and sex differences between adolescents’ perceptions of parental behavioral and psychological control and adolescents’ self-reports of generalized anxiety disorder (GAD) and separation anxiety disorder (SAD) symptoms. The study focused on 1,313 Dutch adolescents (early-to-middle cohort n = 923, 70.3%; middle-to-late cohort n = 390, 29.7%) from the general population. A multi-group, structural equation model was employed to analyze the direction of the effects between behavioral control, psychological control and GAD and SAD symptoms for the adolescent cohorts. The current study demonstrated that a unidirectional child effect model of the adolescents’ GAD and SAD symptoms predicting parental control best described the data. Additionally, adolescent GAD and SAD symptoms were stronger and more systematically related to psychological control than to behavioral control. With regard to age–sex differences, anxiety symptoms almost systematically predicted parental control over time for the early adolescent boys, whereas no significant differences were found between the late adolescent boys and girls