As hypothesized, Total ASI scores were positively correlated with task-related activation within the right middle/anterior insular cortex during masked presentations of fearful versus neutral faces, but not for the other affect conditions. Furthermore, the relationship between AS and BOLD responses in the right insula was maintained even when the effects of state and trait anxiety were statistically controlled in the model and did not differ between HC and SAP groups. Notably, the correlation was driven predominantly by sensitivity to the Physical Concerns of anxiety, whereas Mental Incapacitation and Social Concerns were unrelated to insular activation. In contrast, activation within the other regions (i.e., left insula, right and left amygdala) was unrelated to ASI scores, suggesting that the association was specific to right insular responses rather than limbic and paralimbic activation more generally.
Interestingly, neither the insula nor the amygdala showed significant main effects of affect condition generally. In other words, without consideration of ASI scores, the task-related activation to each contrast condition was modest and did not survive correction for multiple comparisons. Instead, the present findings suggest that only the magnitude of the right insular response to the Masked Fear versus Neutral contrast is directly related to the severity of AS, particularly those aspects that involve apprehensions about the physical sensations of an anxious reaction. It is also notable that the correlation was only present for the Masked Fear versus Masked Neutral condition, suggesting that the relationship between AS and insular responsivity may also depend on the presence of implicit cues related to potential threat in the environment. The fact that the insular response derived from the Masked Fear versus Masked Happy contrast did not show a significant correlation with AS also raises the possibility that the effect may be driven partly by the level of emotional arousal communicated by the faces in addition to the negative valence of the expression (i.e., both fearful and happy expressions share high emotional arousal despite differing in valence). Further research will be necessary to clarify this issue.
For the present study, we chose to examine the relationship between ASI and insular responses in healthy individuals as well as in a psychiatric comparison group meeting diagnostic criteria for specific phobia of small animals. In contrast to panic disorder, which is characterized by severe anxiety reactions across a spectrum of situations and clearly linked to AS (Naragon-Gainey 2010
), specific phobia is a relatively mild and circumscribed anxiety disorder whose relationship to AS is virtually unexplored. Contrary to our predictions, we found no group differences in ASI scores or in the responsiveness of the insula and amygdala to any of the masked affect conditions. Moreover, the linear relationship between ASI scores and insular activation was decidedly similar for both the HC and SAP groups, suggesting that greater fear of the sensations and thoughts of anxiety was associated with increased activation of the insular cortex in response to masked fearful faces, regardless of anxiety disorder status. Prior research has suggested that individuals with SAP are likely to report that their focus of apprehension is most often directed toward physical sensations elicited by the feared animal, such as disgust or revulsion (Lipsitz et al. 2002
). The presently observed correlation between right insular responses and the Physical Concerns factor is consistent with the tendency for SAP patients to focus excessively on the physical responses that emerge when thinking about or confronted with the object of their phobia (e.g., feeling “creeped out” or “disgusted”). Although speculative, it seems likely that the association between insular activity and AS would be exaggerated among individuals with panic disorder, a condition involving excessive focus on the somatic/interoceptive sensations of anxiety (Barlow 2002
; Clark 1986
; McNally 1990
), and which is associated with morphometric abnormalities within the insular cortex (Graeff and Del-Ben 2008
The present findings are consistent with the hypothesized role of the insula in the manifestation of AS (Paulus and Stein 2006
), as well as the broader involvement of the insula in a variety of neuropsychiatric disorders (Nagai et al. 2007
). The insular cortex is believed to be centrally involved in monitoring interoceptive cues reflecting the physiological status of the body, integrating those sensations with expectations for future body states, and producing anticipatory signals regarding the discrepancy between the observed and expected body state to alert other cognitive and affective processing regions (Paulus and Stein 2006
). Individuals with particularly elevated responsiveness of the insula to salient stimuli are hypothesized to experience an exaggerated “interoceptive prediction signal,” which increases the perceived discrepancy between the observed and expected body state (Paulus and Stein 2006
). This discrepancy is believed to generate anticipatory anxiety in sensitive individuals, a factor that may contribute to the effectiveness of aversive conditioning and predispose the development of anxiety disorders (Reiss 1991
). The present findings support this model, demonstrating that greater responses within the right anterior/middle insula to masked fear versus neutral faces were in fact associated with higher scores on the ASI. The present results also build upon recent findings showing that individuals scoring high on the trait of AS tend to show significantly greater insular responses during a simple facial affect matching task compared to individuals with AS scores in the average range (Stein et al. 2007
) and are consistent with recent evidence suggesting that the cortical thickness of the right insula is correlated with AS among individuals with SAP but not healthy controls (Rosso et al. 2010
The positive correlation between BOLD signal differences in the insula and ASI should also be considered in light of the nature of the masked affective stimuli used in the present study. This paradigm minimizes the effects of top down modulation of affective responses by prefrontal regions (Rauch et al. 2000
), permitting an assessment of automatic affective responses with minimal influences from conscious processing. Here, variation in AS was associated with automatic insular responses during fearful affect perception, even without explicit awareness of the emotion expressed on the faces. Building on the recent work of Stein and colleagues (Paulus and Stein 2006
; Stein et al. 2007
), the present findings suggest that not only does AS have the potential to influence an individual's responses to affective stimuli when they are consciously and overtly perceived, but may also affect responses to stimuli that may generally go unnoticed during normal conscious processing. It may be informative for future work to examine whether individuals with high AS might be more easily primed by non-consciously perceived threat-related stimuli and whether this might account for the apparently unpredictable nature of panic symptoms.
The present study is also the first to examine the individual contributions of the three factor subscales of the ASI to the functional brain responses observed during masked affect perception. This study confirmed the hypothesis that fear of physical sensations rather than worries over mental incapacitation or social consequences arising from anxiety would drive much of the association between ASI Total scores and insular activation. Heightened concern regarding the physical sensations of anxiety was associated with greater task-related activation within regions of the brain that are critical to interoceptive monitoring of visceral sensations, bodily states, emotional reactions (Craig 2003
; Wiens 2005
), and the anticipation of impending physical sensations (Lovero et al. 2009
). In fact, when all three ASI scales were considered together, only the Physical Concerns scale contributed significant unique variance to the prediction of insular responses during the masked fear versus neutral condition. In contrast, neither the Mental Incapacitation Concerns nor the Social Concerns subscales were correlated with any voxels within the insula or amygdala. These findings suggest that the relationship between ASI Total and insular activation is driven primarily by concerns related to the physical sensations of anxiety and that amygdala responses appear to be unrelated to the construct of AS, consistent with prior reports on conscious emotional perception (Stein et al. 2007
In conclusion, the present findings support the critical role of the right anterior insula in AS, and further suggest that this effect is driven primarily by worries encompassed by the physical concern features of AS. Moreover, these results indicate that AS is related to insular activation in response to masked affective stimuli, complementing prior studies using overt affective stimuli. Taken together, such findings suggest that the insular responsivity related to AS may extend to visual threat-related stimuli perceived beneath the threshold of conscious awareness.