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.

Figure 1

Anticipation of unpredictable threat task. (a) During the task, participants explored two contexts, one in which there was a threat of receiving a transcutaneous stimulation at any time (T), and one in which they were safe from receiving any stimulation (S). The acronyms colored in red denote contextual epochs in which unsignaled electrical stimulations were administered, which were limited to one to two threat contexts per run of fMRI scanning. (b) Still pictures of the computer-simulated rooms that served as threat and safe contexts. fMRI, functional magnetic resonance imaging.

Figure 2

Adult nonclinical subjects exhibited increased hemodynamic activity in (a and b) the dorsal (dAI) and ventral (vAI) regions of anterior insula, (c) anterior midcingulate cortex (aMCC) and (d) the bed nucleus of the stria terminalis (BNST; indicated by green triangles) during anticipation of unpredictable threat (threat > safe). To the right are plots depicting the peristimulus time courses of the hemodynamic response in each region. Following a brief delay in the hemodynamic response to context onset, all the four regions showed greater sustained activation during the threat context compared with the safe context. All the results shown were corrected for multiple comparisons at P_corr<0.01. L, left; PCC, posterior cingulate cortex; pMCC, posterior midcingulate cortex.

Figure 3

(a and b) Dorsal anterior insula (dAI) activation is positively correlated with anxiety proneness and negatively correlated with perceived control. (c) Anxiety proneness, as measured by trait anxiety scores, is inversely correlated with perceived control over aversive events. The numeral two indicates two overlapping data points. (d) Increased activity in anterior midcingulate cortex (aMCC) was associated with greater exploratory behavior in the threat context. Activation values on the y axis are beta coefficients representing mean percent signal change during anticipation of unpredictable threat (threat > safe). (e) Schematic representation of the mediation model. The pathway from STAI-T to ACQ-R (path a) and then from ACQ-R to dorsal anterior insula (path b) represents the indirect effect of anxiety proneness on dAI activity through perceived control (quantified as the product of paths a and b). The pathway from STAI-T to dAI (path c') represents the direct effect of anxiety proneness on dAI activity. Model coefficients are reported in unstandardized form, thus they map directly onto the measurement scales used. A 95% confidence interval (CI) for the indirect effect (ab) does not contain and is entirely above zero, thus providing evidence that perceived control serves as a mediator of the effect of anxiety proneness on dAI activity. ACQ-R, Anxiety Control Questionnaire-Revised; STAI-T, Spielberger State-Trait Anxiety Inventory.