Research report
Structural correlates of trait anxiety: Reduced thickness in medial orbitofrontal cortex accompanied by volume increase in nucleus accumbens

https://doi.org/10.1016/j.jad.2011.06.003Get rights and content

Abstract

Structural deficiencies within the medial prefrontal cortex have been shown in anxiety-related psychiatric disorders such as panic disorder, post traumatic stress disorder and obsessive compulsive disorder. In healthy subjects, trait anxiety as the individual's disposition to experience anxiety-relevant feelings or thoughts has been shown to be a risk factor for psychiatric disorders. We aimed at exploring the structural correlates of trait anxiety in normal participants. We acquired high-resolution MRI scans from 34 subjects and used FreeSurfer to obtain a measure of cortical thickness. We correlated cortical thickness with self-rated trait anxiety in a whole brain analysis. Automatic subcortical segmentations of the FreeSurfer pipeline were used to relate nucleus accumbens (NAcc) and amygdala volume to trait anxiety.

Trait anxiety was negatively correlated with cortical thickness in the right medial orbitofrontal cortex (mOFC) and positively correlated with the bilateral volume of NAcc. Cortical thickness measures extracted from mOFC were negatively associated with the volume of left NAcc. Since, like in anxiety-related psychiatric disorders, in the healthy sample studied here, trait anxiety was associated with a reduction of cortical thickness in mOFC we suggest that this thinning is a structural precondition rather than a consequence of psychiatric illnesses.

Introduction

Personality traits, such as trait anxiety, are regarded as stable and biological predispositions (Rauch et al., 2005). Trait anxiety in normal subjects has been shown to be closely related to pathological anxiety (Chambers et al., 2004) and may increase the risk of psychiatric disorders (Bienvenu et al., 2001). Trait anxiety reflects an individual's disposition to experience anxiety-relevant feelings or thoughts or to show anxiety-related behaviors (Spielberger, 1983). Overall it comprises the tendency to respond fearfully to a wide variety of unspecific stressors (Spielberger, 1972). Since trait anxiety is regarded as a stable factor with a biological underpinning, we set out to explore its structural correlates. Previous volumetric studies on anxiety-related psychiatric disorders have consistently stressed the importance of the medial orbitofrontal cortex (mOFC, sometimes referred to as ventromedial prefrontal cortex). Studies on panic disorder have consistently reported volume reductions in mOFC (Asami et al., 2009, Roppongi et al., 2010, Sobanski et al., 2010). Likewise, a study comparing patients suffering from post traumatic stress disorder (PTSD) with individuals exposed to trauma but not having developed PTSD found diminished medial prefrontal cortex, namely in pregenual anterior cingulate and subcalossal cortex (Rauch et al., 2003). Along the same lines obsessive–compulsive disorder (OCD) has been related to orbitofrontal volume reductions (Szeszko et al., 1999). Although the mOFC is not the only structure for which alterations have been reported in anxiety-related psychiatric disorders, this area is consistently found to be deviant in different types of anxiety spectrum disorders.

On the behavioral level anxiety-related personality factors have been associated with enhanced fear conditionability as well as impaired extinction of learned fear (Barrett and Armony, 2009). In classical Pavlovian fear conditioning a neutral stimulus (conditioned stimulus, CS) comes to be evaluated as threatening due to its association with an aversive stimulus (unconditioned stimulus, UCS) and elicits fear (Pavlov, 1927). In fear extinction it is learned that a CS no longer predicts a noxious UCS to which it had previously been associated, leading to inhibition of the conditioned response (CR). Extinction creates a new CS-nonUCS memory trace that competes with the initial fear (CS-UCS) memory (Myers and Davis, 2002). An overactive neuronal fear circuitry and reduced recruitment of prefrontal control have been proposed as neural correlates of facilitated fear conditioning and reduced extinction (Bishop, 2007). The structures mOFC, nucleus accumbens and amygdala have been associated with fear conditioning in humans and rodents (Gottfried et al., 2002, Pezze and Feldon, 2004) and abnormal activation in nucleus accumbens has been observed in PTSD (Sailer et al., 2008, Vythilingam et al., 2009). Previous studies have related retention of extinction memory to the cortical thickness of mOFC (Milad et al., 2005, Rauch et al., 2005). A path analysis by Rauch et al. (2005) revealed that extinction retention mediates the relationship between mOFC thickness and the personality trait extraversion and suggests a path though which brain structures and personality may be interconnected.

The aim of the present study was to relate inter-individual differences in cortical thickness to inter-individual differences in trait anxiety in a healthy sample. To this end we used surface-based morphology analysis. Moreover aimed at relating the cortical thinning associated with trait anxiety to automatically segmented volumes of subcortical structures that have been implicated in fear conditioning (NAcc, amygdala).

Section snippets

Participants

34 subjects were recruited by means of newspaper advertisements. The participants (20 women and 14 men) had a mean age of 30.5 years (ranging from 19 to 47 years). All subjects were free of medical, neurological, and psychiatric disorders — according to personal interviews (Mini-International Neuropsychiatric Interview, Lecurbier et al., 1997) carried out by a psychiatrist. Subjects with a family history (first degree) of axis I disorder were excluded from participation. In addition, exclusion

Results

Across participants the average trait anxiety score was 29.9 (SD = 5.6). There was no significant difference of trait anxiety scores between male and female participants (p > 0.17). The average depression score measured by means of the BDI was 1.2, ranging from 0 to 6 (SD = 1.8, possible maximum score 63) indicating absence of depression.

When computing a whole brain analysis in order to explore brain regions where cortical thickness varies with trait anxiety (controlling for age and sex), we found a

Discussion

We investigated the structural correlates of trait anxiety in normal subjects. We found a negative correlation between trait anxiety and cortical thickness in the right mOFC, more specifically in gyrus rectus. On the subcortical level we found trait anxiety to be positively correlated with the volume of NAcc but not with amygdala volume. Moreover, left NAcc volume was negatively correlated with cortical thickness in the mOFC.

The location within the mOFC where the reduction of cortical thickness

Role of funding source

The funding agencies had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest

SK is a Postdoctoral Fellow of the Research Foundation Flanders (FWO). JG has received research funding from the German Federal Ministry of Education and Research (BMBF 01GS08159), research funding from AstraZeneca, Eli Lilly & Co, Janssen-Cilag, Bristol-Myers Squibb and speaker fees from AstraZeneca, Janssen-Cilag, and Bristol-Myers Squibb. FS reports no conflict of interest.

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      The measures of anxiety that were most frequently used by the included studies concerned self-report questionnaires or scales about anxiety-related symptoms/processes (Asami et al., 2018; Blackmon et al., 2011; Brühl et al., 2014; Carnevali et al., 2019; Donzuso et al., 2014; Hattingh, 2011; Kang et al., 2017; Kühn et al., 2011; Maggioni et al., 2019; Molent et al., 2018; Rosso et al., 2010; Syal et al., 2012; Zhao et al., 2017). Considering the self-report measure used to assess anxiety, the STAI or STAI-trait scale was used in five reports (Blackmon et al., 2011; Brühl et al., 2014; Carnevali et al., 2019; Donzuso et al., 2014; Kühn et al., 2011), the HARS in three (Donzuso et al., 2014; Maggioni et al., 2019; Molent et al., 2018), the BAI in two (Blackmon et al., 2011; Kang et al., 2017), the Anxiety Sensitivity Index-Revised (ASI-R) in one (Kang et al., 2017), and the 16-item Anxiety Sensitivity Index (ASI) in one (Rosso et al., 2010). Additionally, self-report measures assessing specific types of anxiety or anxiety-related processes were the following: the Penn State Worry Questionnaire (PSWQ; Carnevali et al., 2019), Panic Disorder Severity Scale (PDSS; Asami et al., 2018; Kang et al., 2017), Liebowitz Social Anxiety Scale (LSAS; Brühl et al., 2014; Hattingh, 2011; Syal et al., 2012; Zhao et al., 2017), Social Phobia Scale (SPS; Brühl et al., 2014), and Social Interaction Anxiety Scale (SIAS; Brühl et al., 2014).

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