Fear of negative evaluation is associated with altered brain function in nonclinical subjects

Highlights

• FNE was associated with weakened functional connectivity in memory-/affect-related regions.

• FNE was associated with decreased betweenness centrality in the right parietal region.

• Graph analysis is useful in investigating the neural underpinnings of social anxiety disorder.

Abstract

Social anxiety disorder (SAD), which involves excessive anxiety and fear of negative evaluation, is accompanied by abnormalities in brain function. While social anxiety appears to be represented on a spectrum ranging from nonclinical behavior to clinical manifestation, neural alteration in nonclinical populations remains unclear. This study examined the relationship between psychological measures of social anxiety, mainly using the Fear of Negative Evaluation Scale (FNES), and brain function (functional connectivity, degree centrality, and regional betweenness centrality). Results showed that FNES scores and functional connectivity of the parahippocampal gyrus and orbitofrontal cortex and the betweenness centrality of the right parietal cortex were negatively correlated. These regions are altered in SAD patients, and each is associated with social cognition and emotional processing. The results supported the perspective that social anxiety occurs on a spectrum and indicated that the FNES is a useful means of detecting neural alterations that may relate to the social anxiety spectrum. In addition, the findings indicated that graph analysis was useful in investigating the neural underpinnings of SAD in addition to other psychiatric symptoms.

Introduction

Social anxiety disorder (SAD) is a chronic psychiatric condition characterized by fear and avoidance of social situations (Goldin et al., 2009a, American Psychiatric Association, 2013). It develops and is maintained via fear of negative evaluation by and expectations of others (Winton et al., 1995, Rapee and Heimberg, 1997). SAD involves emotional distress and functional impairment in work and social domains (Goldin et al., 2009). Furthermore, social anxiety appears to be represented on a spectrum ranging from subclinical behavior (e.g., shyness) to clinical manifestation (SAD; Stein et al., 2007; Stein and Stein, 2008; Miskovic and Schmidt, 2012; Gentili et al., 2015), which may rely on the same underlying dysfunctional mechanisms. However, neural alteration in populations not clinically diagnosed as SAD remains unclear.

In SAD, altered regional activation and functional connectivity have been investigated diligently. For example, relative to nonclinical individuals, SAD patients show greater activation of the subgenual anterior cingulate cortex (sgACC), parahippocampal gyrus (PHG), orbitofrontal cortex (OFC), inferior occipital cortex, and amygdala in response to negative faces (Goldin et al., 2009). In addition, aberrant resting state functional connectivity has been observed in the default mode network (DMN; involves emotional regulation, memory, and self-referential processing), central executive network, and a network that includes the amygdala and insula (Gentili et al., 2009, Liao et al., 2010, Sylvester et al., 2012). Such resting alterations, particularly in the DMN, visual sensorimotor, and affective networks, have been shown to distinguish between clinical and nonclinical SAD populations (Liu et al., 2015). In addition, fear of negative evaluation by others has been associated with activity in the left thalamus and inferior parietal lobule (IPL), particularly during cognitive reappraisal of negative self-beliefs (Goldin et al., 2009).

Although it has been hypothesized that neural alterations in SAD are also associated with the number of properties related to social anxiety in nonclinical populations, few studies have been conducted to examine this issue. To improve current understanding of SAD on a spectrum, we aimed to extract data concerning neural alteration associated with social anxiety in a nonclinical population, using functional magnetic resonance imaging (fMRI).

Functional connectivity and graph-based network analysis have evolved into potentially powerful tools with which to study the relationship between brain network and neuropsychological properties (Menon, 2011, Satterthwaite and Baker, 2015). While functional connectivity analysis allows us to investigate changes in brain organization by quantifying the strength of the connectivity itself, graph analysis describes topological properties of functional networks consisting of nodes (i.e., brain regions) and edges (i.e., functional connectivity between regions), which reveals the relationships between properties of regions and symptoms in a resting state (Bullmore and Sporns, 2009, Meng et al., 2014). With respect to graph analysis measures, we focused on degree centrality and betweenness centrality to ensure simplicity in understanding and performance (Lord et al., 2012; Wee et al., 2014; Shen et al., 2015). Degree centrality represents the number of links connected to an individual node, which means that high-degree nodes interact with numerous other nodes in the network. In contrast, betweenness centrality is defined as a fraction of all of the shortest network paths that pass through a given node, reflecting efficiency of information flow (Rubinov and Sporns, 2010). Both metrics are consistent and stable in the healthy human brain but highly vulnerable to pathological conditions (Palaniyappan and Liddle, 2014) such as depression (Shen et al., 2015), Alzheimer's disease (Tijms et al., 2014), and autism spectrum disorder (Redcay et al., 2013). Therefore, they may allow for sensitive detection of neural alteration on the social anxiety spectrum.

The current study aimed to reveal the neural alterations associated with the number of properties related to social anxiety in a nonclinical population by examining the relationships between the properties of social anxiety and network function represented by functional connectivity and nodal centrality. We made the following predictions: (1) Because decreases or increases in functional alteration in regions related to attentional control and the DMN have frequently been observed in SAD (Gentili et al., 2009, Liao et al., 2010, Sylvester et al., 2012) and reflect symptom severity (Liu et al., 2015), we predicted that they would be altered, even in nonclinical populations. (2) We also expected few correlations between situation-specific anxiety and brain function; because the resting state does not necessarily represent performance-specific alteration (Liu et al., 2015), situation-specific anxiety forms aspects of SAD with varying intensity. In contrast, we predicted that fear of negative evaluation would be associated with functional alteration in SAD, because it is a fundamental, core symptom across all types of SAD.