Increased anterior insula activity in anxious individuals is linked to diminished perceived control

Abstract

Individuals with high-trait anxiety frequently report decreased perceived control. However, it is unclear how these processes are instantiated at a neural level. Prior research suggests that individuals prone to anxiety may have exaggerated activity in the anterior insula and altered activity in the cingulate cortex during anticipation of aversive events. Thus, we hypothesized that anxiety proneness influences anterior insula activation during anticipation of unpredictable threat through decreased perceived control. Forty physically healthy adults underwent neuroimaging while they explored computer-simulated contexts associated either with or without the threat of an unpredictable shock. Skin conductance, anxiety ratings and blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging were used to assess responses to threat versus no threat. Perceived control was measured using the Anxiety Control Questionnaire-Revised. Mediation analysis examined how anxiety proneness influenced BOLD activity. Anticipation of unpredictable threat resulted in increased skin conductance responses, anxiety ratings and enhanced activation in bilateral insula, anterior midcingulate cortex (aMCC) and bed nucleus of the stria terminalis. Individuals with greater anxiety proneness and less perceived control showed greater activity in dorsal anterior insula (dAI). Perceived control mediated the relationship between anxiety proneness and dAI activity. Increased dAI activity was associated with increased activity in aMCC, which correlated with increased exploratory behavior. Results provide evidence that exaggerated insula activation during the threat of unpredictable shock is directly related to low perceived control in anxiety-prone individuals. Perceived control thus may constitute an important treatment target to modulate insula activity during anxious anticipation in anxiety-disordered individuals.

Altered Insula Connectivity under MDMA

“…We observed alterations in functional connectivity between the placebo and MDMA condition in many clusters overlapping with the HarvardOxford Atlas (Supplementary Information S1), notably including the right insular cortex (Figure 2a). All further analyses used the insula cluster revealed by the ICC as a seed ROI because it was selected by a prior application of the ICC (Martuzzi et al, 2011), decreased right insular connectivity was strikingly absent from previous fMRI analyses applied to this data set (Carhart-Harris et al, 2015;Roseman et al, 2014), and the insula plays a crucial role in both subjective feelings of the body (Craig, 2002;2009;2010;Critchley et al, 2004) and anxiety (Alvarez et al, 2015;Grupe and Nitschke, 2013;Paulus and Stein, 2006).…”

“…Seeley et al, 2007, have previously demonstrated increased connectivity in the salience network (dACC and dorsolateral prefrontal cortex) in association with pre-scan anxiety, interpreted as evidence of trait anxiety coded to some degree in the functional architecture of the salience network (2007). Furthermore, alterations in insular functional connectivity following MDMA administration have never been explored despite converging evidence implicating a functional network anchored in the insula in subjective feelings of the body (Craig, 2002;2003;2009;2010; and anxiety (Alvarez et al, 2015;Grupe and Nitschke, 2013;Paulus and Stein, 2006;Seeley et al, 2007). As such, we endeavored to investigate how differences in right insula functional connectivity under MDMA (compared with placebo) might be related to individual differences in trait anxiety.…”

“…These specific items were chosen due to prior literature suggesting the critical involvement of insula functioning in processing bodily sensations (Craig, 2003;Critchley et al, 2004) and trait anxiety (Alvarez et al, 2015;Paulus and Stein, 2006).…”

“…A right insula cluster (Figure 2a; MNI coordinates +46, +04, +02) was selected from this list as a seed ROI for all subsequent analyses as it allowed us to closely follow a prior application of this method (Martuzzi et al, 2011). Furthermore, alterations in insular functional connectivity following MDMA administration have never been explored despite converging evidence implicating a functional network anchored in the insula in subjective feelings of the body Craig, 2002Craig, , 2003Craig, , 2009Craig, , 2010Craig, , 2011 and anxiety (Alvarez et al, 2015;Grupe and Nitschke, 2013;Paulus and Stein, 2006;Seeley et al, 2007). Therefore, there was a firm rationale for selecting this particular region for subsequent seed-based analyses.…”

Recruitment of orbitofrontal cortex during unpredictable threat among adults at risk for affective disorders

“…This research highlights neurocircuits involving the orbitofrontal cortex (OFC), insula, ventromedial prefrontal cortex (vmPFC), amygdala, bed nucleus of the stria terminalis (BNST), and anterior midcingulate cortex (aMCC) (Alvarez et al, 2015;Grupe & Nitschke, 2013;Nitschke, Sarinopoulos, Mackiewicz, Schaefer, & Davidson, 2006). The medial prefrontal cortex (mPFC) has been strongly linked to emotional processing and control of emotional behaviors (Etkin, Egner, & Kalisch, 2011;Phillips, Ladouceur, & Drevets, 2008), while animal research suggests that the right mPFC has a direct role in modulation of stress-regulatory circuits (Sullivan & Gratton, 2002).…”