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Feeling anxious: anticipatory amygdalo-insular response predicts the feeling of anxious anticipation

Feeling anxious: anticipatory amygdalo-insular response predicts the feeling of anxious anticipation doi:10.1093/scan/nsq017 SCAN (2011) 6, 74 ^ 81 Feeling anxious: anticipatory amygdalo-insular response predicts the feeling of anxious anticipation Joshua M. Carlson, Tsafrir Greenberg, Denis Rubin, and Lilianne R. Mujica-Parodi Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, NY, USA Anticipation is a central component of anxiety and the anterior insula appears to be an important neural substrate in which this process is mediated. The anterior insula is also thought to underlie the interoceptive representation of one’s affective state. However, the degree to which individual differences in anticipation-related insula reactivity are associated with variability in the subjective experience of anxious anticipation is untested. To assess this possibility, functional magnetic resonance images were acquired while participants completed an auditory anticipation task with trial-by-trial self-report ratings of anxious anticipation. We hypothesized that the anterior insula would be positively associated with an individual’s subjective experience of anticipatory anxiety. The results provide evidence for an amygdalo-insular system involved in anxious auditory anticipation. Reactivity in the right anterior insula was predictive of individuals’ subjective experience of anxious anticipation for both aversive and neutral stimuli, whereas the amygdala was predictive of anticipatory anxiety for aversive stimuli. In addition, anxious anticipatory activation in the left insula and left amygdala covaried with participants’ level of trait anxiety, particularly when the anticipated event was proximal. Keywords: amygdala; insula; anxiety; anticipation; auditory INTRODUCTION influences this association. Additionally, it is unknown whether this anticipatory insula reactivity is associated with The anticipation of undesirable events is an essential char- variability in the subjective experience of anxious acteristic of anxiety. Although moderate levels of anxious anticipation. anticipation may be adaptive and allow individuals to pre- In addition to the insula, neuroimaging research in pare for negative events, excessive anticipation can lead to healthy populations has revealed that aversive anticipation debilitating disruptions in daily life (Nitschke et al., 2006). involves the amygdala (Phelps et al., 2001; Nitschke et al., Indeed, dysfunctional levels of anticipation appear to man- 2006; Onoda et al., 2008) and areas (including medial, dor- ifest in a number of anxiety disorders including specific solateral, orbitofrontal, ventrolateral and anterior cingulate phobia, generalized anxiety disorder, social anxiety disorder cortex) of the prefrontal cortex (Simpson et al., 2001; and panic disorder. Knowledge about the neural substrates Simmons et al., 2004, 2006; Nitschke et al., 2006; Straube of anxious anticipation in healthy individuals may facilitate et al., 2007; Onoda et al., 2008). It is unclear to what extent our understanding of this process in clinical populations. the neural system(s) involved in the anticipation of aversive Neuroimaging research has consistently implicated the events across sensory domains recruit common and/or insula as an important substrate of anxious anticipation unique neural structures. It would be expected that struc- (Phelps et al., 2001; Simmons et al., 2004; Dalton et al., tures such as the amygdala, which are involved in detecting 2005; Nitschke et al., 2006; Onoda et al., 2008; Waugh and appraising potential threats across sensory modalities et al., 2008), especially in highly anxious samples (LeDoux, 1996; Zald, 2003) would be common in most (Lorberbaum et al., 2004; Simmons et al., 2006; Straube forms of threat detection and aversive anticipation. et al. 2007). Although differences in anxiety are associated However, the structures representing the actual preparatory with anticipatory insula activity (Lorberbaum et al., 2004; response may depend upon the specific anticipated event. In Simmons et al., 2006; Straube et al., 2007), it is unclear particular, the insula is generally involved in the processing how the temporal proximity of the anticipated event of disgust (Phillips et al., 1997; Wright et al., 2004) and interoceptive body states including pain (Craig, 2003), but Received 24 April 2009; Accepted 2 February 2010 the insula is also thought to underlie the conscious percep- Advance Access publication 5 March 2010 This research was supported by the Office of Naval Research #N0014-04-1-005 (LRMP) and the National tion of affective feelings (Critchley et al., 2004). While the Institutes of Health #5M01-RR-10710 (General Clinical Research Center). insula has previously been implicated in the negative antic- Correspondence should be addressed to Dr Joshua M. Carlson, Laboratory for the Study of Emotion and ipation of painful (Phelps et al., 2001) and visual (Simmons Cognition, Department of Biomedical Engineering, Bioengineering Building, SUNY Stony Brook, Stony Brook, NY 11794, USA. E-mail: carlsonjm79@gmail.com et al., 2004; Dalton et al., 2005; Nitschke et al., 2006; Onoda The Author (2010). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com The feeling of anxious anticipation SCAN (2011) 75 et al., 2008; Waugh et al., 2008) stimuli, many negative visual similar to the published normal range for working adults stimuli (e.g. mutilations and insects) have an inherent dis- (Spielberger et al., 1970). Male (M¼ 33.79) and female gust quality and it is therefore unclear whether this insula (M¼ 33.56) participants had equivalent levels of trait anxi- activity reflects a (i) specific preparatory pain or disgust ety (P> 0.1). Participant age was not associated with anxiety response or (ii) general feeling state of anxious anticipation. (P> 0.1). Given that loud bursts (100 dB) of white noise are aversive, but are neither painful nor disgusting, they may serve as a Stimuli and equipment relatively clean stimulus-probe to assess the role of the insula The auditory anticipation task included both auditory events (and other neural structures) in anticipatory anxiety. and visual cues. All visual stimuli were presented using a Here, participants completed a functional magnetic reso- mirror attached to the head coil, which reflected onto a nance imaging (fMRI) task with a cue plus countdown par- screen positioned behind participants while they lay in the adigm, which signaled a future aversive or neutral auditory scanner. Visual stimuli were presented on the screen using an event. Participants rated their level of anxious anticipation MRI-compatible 60 Hz projector with a 1024 768 resolu- during each trial. The primary aim of this study was to assess tion. Auditory stimuli were presented through SereneSound whether individuals’ feelings of anxious anticipation were (Resonance Technology Inc., Northridge, CA, USA) 30 dB associated with their anticipatory insula response. As sec- external noise attenuating MRI-compatible headphones. ondary aims we examined whether the insula and amygdala Auditory and visual stimuli were presented and the task were involved in anticipation of aversive auditory stimuli was programmed with E-Prime 1.2 (Psychology Software and the extent to which anticipatory reactivity in these struc- Tools, Pittsburg, PA, USA). Initiation of the experiment tures is predicted by trait anxiety. We hypothesized that was triggered by the first radiofrequency pulse of the echo self-reports of anxious anticipation would be positively asso- planar imaging (EPI) sequence. ciated with individuals’ insula reactivity during anxious anticipation. In addition, based on previous research dis- Experimental procedure cussed above, we hypothesized that both the insula and the amygdala would be activated during aversive auditory antic- The auditory anticipation task consisted of 20 trials/blocks of ipation and that activity in these areas would be positively anticipation: 10 aversive and 10 neutral. As displayed in associated with individual differences in trait anxiety. Figure 1, each trial began with a white fixation cue presented in the center of a black screen (jittered 4000–8000 ms). The fixation cue was immediately followed by a red ‘X’ or a blue METHODS ‘O’ for 1000 ms. Participants were informed that the red ‘X’ Participants indicated that they would hear a loud (100 dB) burst of white Thirty-five (19 male and 16 female) healthy adults between noise (aversive event), while the blue ‘O’ indicated that they the ages of 18 and 48 (M ¼ 23.91, s.d. ¼ 6.64) participated in would hear a soft (55 dB) presentation of the same white the study. Thirty-one reported being right-handed and four noise (neutral event). Preceding the presentation of aversive reported being left-handed. Potential participants were and neutral events was a 16 s period (block) of anticipation. screened for prescription and recreational drug usage, neu- During this block of anticipation, a countdown from 16 to 1 rological and psychological histories, and for presence of (16 s; red text for aversive and blue for neutral) was numer- metal implants. Advertisements were used for recruitment ically presented in the center of the screen. Aversive and and monetary compensation was provided to participants. neutral auditory events immediately followed this period of This study was approved by the Institutional Review anticipation and were 1000 ms in duration. After the presen- Board of Stony Brook University; all participants provided tation of the aversive or neutral event, a screen appeared informed consent. Twenty-three participants completed the which asked participants to rate their level of anxiety auditory anticipation task with participant feedback 1 during the countdown on a 4-point scale (from 1¼ ‘not described below and 12 completed an alternate version anxious’ to 4¼ ‘very anxious’). that did not contain participant feedback. Image acquisition Assessment of trait anxiety A 3 Tesla Siemens Trio whole body scanner equipped with Prior to scanning, participants completed the trait scale of an eight-channel SENSE head coil was used to acquire the Spielberger State-Trait Anxiety Inventory (Spielberger T2*-weighted scans with an EPI sequence sensitive to et al., 1970). Trait anxiety scores in the current sample BOLD signal using the following parameters: were between 20 and 53 (M¼ 33.69, s.d.¼ 7.34), which is TR¼ 2500 ms, TE¼ 22 ms, flip angle¼ 838, matrix dimen- Twelve participants completed an alternate version of the auditory anticipation task containing 212 sions¼ 96 96, FOV¼ 224 224 mm, slices¼ 36, slice volumes acquired on a separate scanner (Philips 3T) using the same acquisition parameters described in thickness¼ 3.5 mm, gap¼ 0. We additionally acquired ana- the text. This version of the task did not include the participant feedback screen. In place of the feedback tomical T1-weighted structural scans. A total of 232 volumes screen was an additional period of fixation (set at 2000 ms) that followed the auditory event and preceded the beginning of the next trial. were collected during a single functional run. Neutral anticipation (17s) Aversive anticipation (17s) Time . . . . . . 76 SCAN (2011) J. M.Carlson et al. Fixation (mean = 6s) Neutral cue (1s) Neutral (55db) sound (1s) Rate Rating for anxiety experienced during the countdown (4s) Aversive cue (1s) Aversive (100 dB) sound (1s) Rate Fig. 1 Each trial of the anticipation task began with a fixation cue. Fixation was followed by a red ‘X’ or a blue ‘O,’ which respectively, indicated that a loud or soft burst of white noise would be presented after a 16 s countdown. The 17 s period of cue þ countdown was considered a block of either anxious (X cue) or neutral (O cue) anticipation. After the auditory event participants reported the level of anxiety they experienced during the countdown. Image analysis Behavioral data. A paired samples t-test of participants self-reported anxiety ratings during the countdown revealed Standard preprocessing procedures were performed in that overall participants felt more anxious in anticipation SPM5, including image realignment corrections for head of the aversive (M¼ 2.50) relative to the neutral movements, slice timing corrections for order of slice acqui- (M¼ 1.17) sound, t(22)¼ 8.35, P < 0.001. This result serves sition, normalization to standard 2 2 2 mm Montreal as a manipulation check verifying that on average partici- Neurological Institute space, and spatial smoothing with a pants felt more anxious in anticipation of loud relative to Gaussian full-width-at-half-maximum 6 mm filter. Using the soft sounds. general linear model in SPM5, first-level single subject sta- Neural correlations with self-report anxious anticipa- tistical parameter maps were created from a model, which tion states. Participants’ trial-by-trial self-reported anxiety specified both blocks of anticipation (aversive and neutral; ratings was included as regressors in the first-level SPMs. cue þ countdown: 17 s) and auditory events (aversive and Contrast files for these regressors were then used at the neutral; 0 s). Bilateral amygdala and insula masks were cre- second-level to assess whether anticipatory reactivity in our ated using the Masks for Regions of Interest Analysis soft- ROIs was associated with individuals’ subjective experience ware (Walter et al., 2003). Region of interest (ROI) analyses of anxious anticipation. As displayed in Figure 2, the right were preformed using a false discovery rate search volume anterior insula was positively associated with participants’ corrected ¼ 0.05 with an extent threshold¼ 10 continuous self-reported anxiety during both aversive and neutral voxels. trials. On the other hand, the amygdala bilaterally covaried to a greater extent with participants’ self-report anxiety RESULTS during aversive compared to neutral anticipation (see Analyses of participants’ self-reported anticipatory Table 1). Thus, the right anterior insula was associated the anxiety subjective experience of anxious anticipation during both These analyses only included the 23 individuals who com- high- and low-anxiety inducing trials, whereas the amygdala pleted the version of the task with self-reported feedback of was selectively associated with feelings of anxiety during anxious anticipation. highly aversive trials. The feeling of anxious anticipation SCAN (2011) 77 Analyses of aversive auditory anticipation (Figure 3a). Time-series data were extracted for each condi- tion from the active voxels within right amygdala and insula. These analyses include all 35 individuals who completed The data were linearly interpolated, detrended and then either version of the auditory anticipation task. averaged across voxels and trials for each participant. As Aversive auditory anticipation-related activity. An aver- can be seen in Figure 3b, the amygdala and insula responded sive vs neutral anticipation second-level t-test contrast was in a similar fashion where activation was increased in aver- created to assess the neural correlates of aversive auditory sive relative to neutral trials 6 s and sustained throughout anticipation. These ROI analyses revealed that the right the period of anxious anticipation. An additional whole amygdala and bilateral insula were more active during brain analysis of aversive vs neutral anticipation with a periods of aversive compared to neutral anticipation false discovery rate corrected ¼ 0.05 and an extent thresh- old¼ 20 continuous voxels was used for further exploration. X & O Ratings X > O Ratings In addition to the insula and amygdala, a number of other z = –2 y = –2 structures including the left dorsolateral prefrontal cortex Insula (DLPFC), bilateral brainstem/inferior colliculus, medial superior frontal gyrus, and left cerebellum all displayed increased activation during aversive compared to neutral auditory anticipation (see Table 1 for details). Amygdala 2 Correlations with trait anxiety. Trait anxiety was included as a covariate in the ROI analyses to assess the extent to which this variable predicted activity in the amyg- LR dala and insula during the anticipation of aversive sounds. As shown in Figure 4a, trait anxiety was positively associated Fig. 2 Displayed on the left is activity in the right anterior insula that was predictive with anxious anticipatory activation in the left amygdala. At of intertrial differences in participants’ self-reported level of anxious anticipation a reduced threshold of P < 0.005, the left insula was during both aversive and neutral anticipation trials. The amygdala (right panel) uncorrected was bilaterally positively associated with participants’ ratings of anxious anticipation positively associated with trait anxiety. Extracted activity during aversive compared to neutral trials. Activation displayed at P < 0.005 uncorrected from these clusters was linearly interpolated, detrended for illustrative purposes. and then averaged across voxels and trials for each Table 1 Aversive auditory anticiption-related activity MNI Coordinates Maximally activated voxel Analysis and region Hemisphere xyz Voxels t-value P-value Aversive > Neutral anticipation (ROI) Amygdala R 18 2 18 19 4.30 <0.05 SVC Insula L 44 14 4 62 5.57 <0.05 SVC R40 18 8 98 5.13 <0.05 SVC Aversive > neutral anticipation (whole brain) Brainstem/inferior colliculus L 10 32 12 24 5.69 <0.05 FDR R14 28 12 51 5.24 Insula L 44 20 6 163 5.65 <0.05 FDR R40 18 8 42 5.13 <0.05 FDR Amygdala R 16 4 20 23 5.13 <0.05 FDR Superior frontal gyrus L–R 4 8 56 51 5.31 <0.05 FDR Dorsolateral prefrontal cortex L 30 46 28 20 4.52 <0.05 FDR Cerebellum L 22 66 18 50 4.92 <0.05 FDR Trait anxiety (ROI) Amygdala L 30 2 26 31 4.27 <0.05 SVC Insula L 42 16 0 26 3.70 <0.005 uncor X and O ratings (ROI) Insula R 38 12 16 66 4.28 <0.05 SVC X > O ratings (ROI) Amygdala L 24 2 14 23 4.18 <0.05 SVC R26 0 14 28 4.21 <0.05 SVC t-value 78 SCAN (2011) J. M.Carlson et al. Anxious > Neutral Anticipation Covariation with Trait Anxiety (a) (a) z = –8 y = –2 z = –3 y = –2 Insula Insula Amygdala Amygdala L R L R Anxious 2 2 Early (b) (b) 60 Neutral Mid 1 1 Late 0 0 −1 −1 40 40 −2 −2 4 8 12 16 4 8 12 16 Time (sec) Time (sec) 20 20 -4 0 4 8 -5 0 5 10 Fig. 3 (a) The bilateral insula (upper left panel) and right amygdala (upper right panel) were activated across participants during the anxious anticipation of a loud Insula Activation Amygdala Activation sound. Activation displayed at P < 0.001 for illustrative purposes. (b) The uncorrected time-series data indicate an elevated response within both the right insula (lower left Fig. 4 (a) Anxious anticipation-related activity within the left anterior insula (upper panel) and amygdala (lower right panel) during anxious relative to neutral antici- left panel) and amygdala (upper right panel) were sensitive to individual differences pation that begins 6 s post cue and sustains throughout the countdown. in trait anxiety. Individuals with higher levels of anxiety also had higher levels of activation in the left anterior insula and amygdala during aversive relative to neutral anticipation trials. Activation displayed at P < 0.005 for illustrative purposes. uncorrected (b) Trait anxiety was significantly correlated with insula (lower left panel) reactivity participant. The first 2 s of these interpolated time-series during the late (r¼ 0.36, P < 0.05), but not early (r¼0.13, P > 0.1) or middle (r¼ 0.18, P > 0.1), phases of aversive anticipation. Amygdala (lower right panel) were discarded, while the remaining 15 s was split into activity correlated with trait anxiety during the middle (r¼ 0.39, P < 0.05) and late early (3–7 s), middle (8–12 s) and late (13–17 s) phases of (r¼ 0.35, P < 0.05), but not early (r¼ 0.24, P > 0.1) phases of anticipation. anticipation. Trait anxiety was positively correlated with left amygdala activity during the middle (r¼ 0.39, P < 0.05) and late (r¼ 0.35, P < 0.05) phases of anticipation. The left anticipation. Furthermore, activation in the amygdala and insula positively correlated with trait anxiety during the late insula is predictive of an individual’s feeling state of (r¼ 0.36, P < 0.05), but not middle (r¼ 0.17, P > 0.1), phase anxious anticipation. of anticipation (see Figure 4b). Neither structure was asso- ciated with trait anxiety for the early phase of anticipation Role of the amygdala and insula in feeling (amygdala: r¼ 0.24, P > 0.1, insula: r¼0.13, P > 0.1). anticipatory anxiety The right anterior insula was sensitive to variability in DISCUSSION individuals’ anxious feelings during anticipation which is Participants’ feelings of anxiety were positively associated consistent with its proposed role in conscious awareness of with activation in the right anterior insula during anticipa- one’s own feeling states (Craig, 2003; Critchley et al., 2004). tion of both aversive and neutral sounds. Conversely, acti- Unlike the insula, amygdala activity was only associated with vation in the amygdala positively covaried with anxious variability in individual’s feeling states during anxious (rela- feelings, but only during anxious anticipation (Figure 2). tive to neutral) anticipation. That is, the degree to which an In addition, the right amygdala and bilateral insula were individual’s amygdala response was predictive of their generally activated during periods of anxious auditory antic- self-reported level of anxious anticipation was restricted to ipation (Figure 3). Anxious anticipation-related activation the aversive/loud sound trials. Given that the amygdala is of the left amygdala and insula were positively associated known to elicit and modulate physiological responses to with individual differences in trait anxiety (Figure 4). threat (Davis and Whalen, 2001; LeDoux, 1996) and that These findings suggest that across individuals there is an physiological responses contribute to one’s feeling state amygdalo-insular network for the anticipation of negative (Craig, 2003), the amygdala may play an indirect role in events and that activity within this network is relatively ele- modulating individuals’ feeling states in highly arousing vated in highly anxious individuals during aversive auditory circumstances. Indeed, models of amygdala functionality Mean Intensity t-value Trait Anxiety t -value The feeling of anxious anticipation SCAN (2011) 79 (Davis and Whalen, 2001; LeDoux, 1996) do not view this undesirable event. Indeed, another fMRI study of aversive structure as the neural substrate underlying the subjective anticipation utilizing the countdown methodology also did experience of emotion (or even specifically fear). On the not report activations in the anterior cingulate (Phelps et al., other hand, the anterior insula was predictive of participants’ 2001). Previous research indicates that the ACC is involved feeling states in both low and high arousal conditions, which in conflict monitoring and the processing of expectations suggests that activation in the insula is more generally pre- (Botvinick, 2007; Sallet et al., 2007). In anticipation para- dictive of one’s internal feelings. Taken together the findings digms the ACC may play a similar role where the ACC ‘mon- in this study and previous research (Craig, 2003; Critchley itors’ ones expectations about the temporal proximity of the et al., 2004) suggest a general role of the insula in the pro- anticipated aversive event. However, future research that cessing and representation of one’s internal feeling state, directly manipulates temporal certainty is needed to test while the amygdala may play a more specific role in contri- this speculative role of the ACC. buting to anxious worry states by modulating physiological In addition to the amygdala and insula, the left DLPFC, responding under conditions of high arousal. bilateral brainstem/inferior colliculus, medial superior fron- tal gyrus and left cerebellum were all activated during anx- ious auditory anticipation. The extent to which each Neural correlates of aversive auditory anticipation component of this anticipatory system is involved in differ- To the best of our knowledge, the current findings provide ent anticipatory situations is unknown. Although it is the first evidence that the right amygdala and bilateral insula unclear whether the BOLD signal reflects local inhibitory are activated during periods of anxious auditory anticipa- or excitatory neuronal activity, it may be expected that in tion. The finding of anticipatory insula reactivity to an aver- anticipation of a loud sound a general dampening or gating sive auditory stimulus, which was neither disgusting nor of auditory processing would be adaptive. Consistent with painful, suggests that the role of the insula in aversive antic- this notion, we found that activity in the inferior colliculus ipation is not that of a specific preparatory response to dis- was modulated by aversive auditory anticipation, which may gust or pain. Rather, our findings suggest that the role of the represent subcortical gating of auditory processing. The insula in aversive anticipation appears to be more consistent DLPFC activation is consistent with previous findings of with its previously implicated role in mediating interoceptive anticipatory PFC activations (Simpson et al., 2001; representations (Craig, 2003) and conscious affective feeling Simmons et al., 2004, 2006; Nitschke et al., 2006; Straube states (Critchley et al., 2004). On the other hand, the amyg- et al., 2007; Onoda et al., 2008). Activation in this region is dala is known to be sensitive to a variety of threatening also implicated in cognitive reappraisal (Ochsner et al., stimuli including social (Morris et al., 1996) and fear con- 2002) and may indicate an unsolicited attempt of partici- ditioned (Knight et al., 2005) cues. The amygdala response pants to regulate their anticipatory response. Thus, similar to to potential threat appears to rely upon limited sensory other sensory modalities, aversive auditory anticipation information (Morris et al., 1998; Whalen et al., 1998; recruits a distributed network of brain structures including Pasley et al., 2004; Williams et al., 2004) and results in a the amygdala, insula, and DLPFC among others, but also rapid modulation of physiology (Morris et al., 1998) and recruits auditory specific structures such as the inferior attention-related behavior including modulations of sensory colliculus. cortex (Carlson et al., 2009). Given the characteristics of the amygdala and insula as well as the similar time course of the Association with trait anxiety anxious anticipation-related reactivity in these structures (see Figure 3b), we speculate that these two affective pro- Anxious anticipation-related activation of the left amygdala cesses may occur in parallel. That is, during periods of anx- and insula were positively associated with individual differ- ious anticipation the amygdala may detect threat cues and ences in trait anxiety. Although anxiety-amygdala associa- initiate the fear response including modulations in physiol- tions have been observed in paradigms designed to elicit automatic responses (Rauch et al., 2000; Etkin et al., 2004; ogy and attention. At the same time (at least at the temporal Armony et al., 2005; Bryant et al., 2008), these associations resolution of fMRI), visceral changes associated with this have also been reported in anticipation paradigms response are represented within the insula and contribute to an anxious feeling state of aversive anticipation, which (Lorberbaum et al., 2004). Previous research has also indi- may in turn modulate processing in the amygdala. cated that the insula is elevated in high anxiety individuals Surprisingly, we did not find activation in the anterior during aversive anticipation (Lorberbaum et al., 2004; cingulate cortex (ACC), a region which has previously Simmons et al., 2006; Straube et al., 2007). Thus, the been shown to be activated during aversive anticipation observed anxiety associations in the amygdala and insula (Nitschke et al., 2006; Straube et al., 2007; Onoda et al., during aversive anticipation are consistent with previous 2008). This may be due to the methodology we employed findings and indicate an elevated anticipatory response in to assess anxious auditory anticipation. In particular, the anxiety. Here, we add to this literature with our finding of countdown in our study may have reduced or eliminated an elevated amygdala response in highly trait anxious indi- the temporal uncertainty associated with the anticipated viduals that starts in the middle and is maintained into the 80 SCAN (2011) J. M.Carlson et al. Dalton, K.M., Kalin, N.H., Grist, T.M., Davidson, R.J. (2005). Neural-car- late phase of aversive anticipation. In contrast, insula reac- diac coupling in threat-evoked anxiety. Journal of Cognitive Neuroscience, tivity was only associated with trait anxiety during the late 17(6), 969–80. phase of anticipation. These results indicate that in highly Davis, M., Whalen, P.J. (2001). The amygdala: vigilance and emotion. anxious individuals there is a relatively early sustained amyg- Molecular Psychiatry, 6(1), 13–34. dala sensitivity to anticipated threat that is accompanied by a Etkin, A., Klemenhagen, K.C., Dudman, J.T., Rogan, M.T., Hen, R., Kandel, E.R., et al. (2004). 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Feeling anxious: anticipatory amygdalo-insular response predicts the feeling of anxious anticipation

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doi:10.1093/scan/nsq017 SCAN (2011) 6, 74 ^ 81 Feeling anxious: anticipatory amygdalo-insular response predicts the feeling of anxious anticipation Joshua M. Carlson, Tsafrir Greenberg, Denis Rubin, and Lilianne R. Mujica-Parodi Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, NY, USA Anticipation is a central component of anxiety and the anterior insula appears to be an important neural substrate in which this process is mediated. The anterior insula is also thought to underlie the interoceptive representation of one’s affective state. However, the degree to which individual differences in anticipation-related insula reactivity are associated with variability in the subjective experience of anxious anticipation is untested. To assess this possibility, functional magnetic resonance images were acquired while participants completed an auditory anticipation task with trial-by-trial self-report ratings of anxious anticipation. We hypothesized that the anterior insula would be positively associated with an individual’s subjective experience of anticipatory anxiety. The results provide evidence for an amygdalo-insular system involved in anxious auditory anticipation. Reactivity in the right anterior insula was predictive of individuals’ subjective experience of anxious anticipation for both aversive and neutral stimuli, whereas the amygdala was predictive of anticipatory anxiety for aversive stimuli. In addition, anxious anticipatory activation in the left insula and left amygdala covaried with participants’ level of trait anxiety, particularly when the anticipated event was proximal. Keywords: amygdala; insula; anxiety; anticipation; auditory INTRODUCTION influences this association. Additionally, it is unknown whether this anticipatory insula reactivity is associated with The anticipation of undesirable events is an essential char- variability in the subjective experience of anxious acteristic of anxiety. Although moderate levels of anxious anticipation. anticipation may be adaptive and allow individuals to pre- In addition to the insula, neuroimaging research in pare for negative events, excessive anticipation can lead to healthy populations has revealed that aversive anticipation debilitating disruptions in daily life (Nitschke et al., 2006). involves the amygdala (Phelps et al., 2001; Nitschke et al., Indeed, dysfunctional levels of anticipation appear to man- 2006; Onoda et al., 2008) and areas (including medial, dor- ifest in a number of anxiety disorders including specific solateral, orbitofrontal, ventrolateral and anterior cingulate phobia, generalized anxiety disorder, social anxiety disorder cortex) of the prefrontal cortex (Simpson et al., 2001; and panic disorder. Knowledge about the neural substrates Simmons et al., 2004, 2006; Nitschke et al., 2006; Straube of anxious anticipation in healthy individuals may facilitate et al., 2007; Onoda et al., 2008). It is unclear to what extent our understanding of this process in clinical populations. the neural system(s) involved in the anticipation of aversive Neuroimaging research has consistently implicated the events across sensory domains recruit common and/or insula as an important substrate of anxious anticipation unique neural structures. It would be expected that struc- (Phelps et al., 2001; Simmons et al., 2004; Dalton et al., tures such as the amygdala, which are involved in detecting 2005; Nitschke et al., 2006; Onoda et al., 2008; Waugh and appraising potential threats across sensory modalities et al., 2008), especially in highly anxious samples (LeDoux, 1996; Zald, 2003) would be common in most (Lorberbaum et al., 2004; Simmons et al., 2006; Straube forms of threat detection and aversive anticipation. et al. 2007). Although differences in anxiety are associated However, the structures representing the actual preparatory with anticipatory insula activity (Lorberbaum et al., 2004; response may depend upon the specific anticipated event. In Simmons et al., 2006; Straube et al., 2007), it is unclear particular, the insula is generally involved in the processing how the temporal proximity of the anticipated event of disgust (Phillips et al., 1997; Wright et al., 2004) and interoceptive body states including pain (Craig, 2003), but Received 24 April 2009; Accepted 2 February 2010 the insula is also thought to underlie the conscious percep- Advance Access publication 5 March 2010 This research was supported by the Office of Naval Research #N0014-04-1-005 (LRMP) and the National tion of affective feelings (Critchley et al., 2004). While the Institutes of Health #5M01-RR-10710 (General Clinical Research Center). insula has previously been implicated in the negative antic- Correspondence should be addressed to Dr Joshua M. Carlson, Laboratory for the Study of Emotion and ipation of painful (Phelps et al., 2001) and visual (Simmons Cognition, Department of Biomedical Engineering, Bioengineering Building, SUNY Stony Brook, Stony Brook, NY 11794, USA. E-mail: carlsonjm79@gmail.com et al., 2004; Dalton et al., 2005; Nitschke et al., 2006; Onoda The Author (2010). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com The feeling of anxious anticipation SCAN (2011) 75 et al., 2008; Waugh et al., 2008) stimuli, many negative visual similar to the published normal range for working adults stimuli (e.g. mutilations and insects) have an inherent dis- (Spielberger et al., 1970). Male (M¼ 33.79) and female gust quality and it is therefore unclear whether this insula (M¼ 33.56) participants had equivalent levels of trait anxi- activity reflects a (i) specific preparatory pain or disgust ety (P> 0.1). Participant age was not associated with anxiety response or (ii) general feeling state of anxious anticipation. (P> 0.1). Given that loud bursts (100 dB) of white noise are aversive, but are neither painful nor disgusting, they may serve as a Stimuli and equipment relatively clean stimulus-probe to assess the role of the insula The auditory anticipation task included both auditory events (and other neural structures) in anticipatory anxiety. and visual cues. All visual stimuli were presented using a Here, participants completed a functional magnetic reso- mirror attached to the head coil, which reflected onto a nance imaging (fMRI) task with a cue plus countdown par- screen positioned behind participants while they lay in the adigm, which signaled a future aversive or neutral auditory scanner. Visual stimuli were presented on the screen using an event. Participants rated their level of anxious anticipation MRI-compatible 60 Hz projector with a 1024 768 resolu- during each trial. The primary aim of this study was to assess tion. Auditory stimuli were presented through SereneSound whether individuals’ feelings of anxious anticipation were (Resonance Technology Inc., Northridge, CA, USA) 30 dB associated with their anticipatory insula response. As sec- external noise attenuating MRI-compatible headphones. ondary aims we examined whether the insula and amygdala Auditory and visual stimuli were presented and the task were involved in anticipation of aversive auditory stimuli was programmed with E-Prime 1.2 (Psychology Software and the extent to which anticipatory reactivity in these struc- Tools, Pittsburg, PA, USA). Initiation of the experiment tures is predicted by trait anxiety. We hypothesized that was triggered by the first radiofrequency pulse of the echo self-reports of anxious anticipation would be positively asso- planar imaging (EPI) sequence. ciated with individuals’ insula reactivity during anxious anticipation. In addition, based on previous research dis- Experimental procedure cussed above, we hypothesized that both the insula and the amygdala would be activated during aversive auditory antic- The auditory anticipation task consisted of 20 trials/blocks of ipation and that activity in these areas would be positively anticipation: 10 aversive and 10 neutral. As displayed in associated with individual differences in trait anxiety. Figure 1, each trial began with a white fixation cue presented in the center of a black screen (jittered 4000–8000 ms). The fixation cue was immediately followed by a red ‘X’ or a blue METHODS ‘O’ for 1000 ms. Participants were informed that the red ‘X’ Participants indicated that they would hear a loud (100 dB) burst of white Thirty-five (19 male and 16 female) healthy adults between noise (aversive event), while the blue ‘O’ indicated that they the ages of 18 and 48 (M ¼ 23.91, s.d. ¼ 6.64) participated in would hear a soft (55 dB) presentation of the same white the study. Thirty-one reported being right-handed and four noise (neutral event). Preceding the presentation of aversive reported being left-handed. Potential participants were and neutral events was a 16 s period (block) of anticipation. screened for prescription and recreational drug usage, neu- During this block of anticipation, a countdown from 16 to 1 rological and psychological histories, and for presence of (16 s; red text for aversive and blue for neutral) was numer- metal implants. Advertisements were used for recruitment ically presented in the center of the screen. Aversive and and monetary compensation was provided to participants. neutral auditory events immediately followed this period of This study was approved by the Institutional Review anticipation and were 1000 ms in duration. After the presen- Board of Stony Brook University; all participants provided tation of the aversive or neutral event, a screen appeared informed consent. Twenty-three participants completed the which asked participants to rate their level of anxiety auditory anticipation task with participant feedback 1 during the countdown on a 4-point scale (from 1¼ ‘not described below and 12 completed an alternate version anxious’ to 4¼ ‘very anxious’). that did not contain participant feedback. Image acquisition Assessment of trait anxiety A 3 Tesla Siemens Trio whole body scanner equipped with Prior to scanning, participants completed the trait scale of an eight-channel SENSE head coil was used to acquire the Spielberger State-Trait Anxiety Inventory (Spielberger T2*-weighted scans with an EPI sequence sensitive to et al., 1970). Trait anxiety scores in the current sample BOLD signal using the following parameters: were between 20 and 53 (M¼ 33.69, s.d.¼ 7.34), which is TR¼ 2500 ms, TE¼ 22 ms, flip angle¼ 838, matrix dimen- Twelve participants completed an alternate version of the auditory anticipation task containing 212 sions¼ 96 96, FOV¼ 224 224 mm, slices¼ 36, slice volumes acquired on a separate scanner (Philips 3T) using the same acquisition parameters described in thickness¼ 3.5 mm, gap¼ 0. We additionally acquired ana- the text. This version of the task did not include the participant feedback screen. In place of the feedback tomical T1-weighted structural scans. A total of 232 volumes screen was an additional period of fixation (set at 2000 ms) that followed the auditory event and preceded the beginning of the next trial. were collected during a single functional run. Neutral anticipation (17s) Aversive anticipation (17s) Time . . . . . . 76 SCAN (2011) J. M.Carlson et al. Fixation (mean = 6s) Neutral cue (1s) Neutral (55db) sound (1s) Rate Rating for anxiety experienced during the countdown (4s) Aversive cue (1s) Aversive (100 dB) sound (1s) Rate Fig. 1 Each trial of the anticipation task began with a fixation cue. Fixation was followed by a red ‘X’ or a blue ‘O,’ which respectively, indicated that a loud or soft burst of white noise would be presented after a 16 s countdown. The 17 s period of cue þ countdown was considered a block of either anxious (X cue) or neutral (O cue) anticipation. After the auditory event participants reported the level of anxiety they experienced during the countdown. Image analysis Behavioral data. A paired samples t-test of participants self-reported anxiety ratings during the countdown revealed Standard preprocessing procedures were performed in that overall participants felt more anxious in anticipation SPM5, including image realignment corrections for head of the aversive (M¼ 2.50) relative to the neutral movements, slice timing corrections for order of slice acqui- (M¼ 1.17) sound, t(22)¼ 8.35, P < 0.001. This result serves sition, normalization to standard 2 2 2 mm Montreal as a manipulation check verifying that on average partici- Neurological Institute space, and spatial smoothing with a pants felt more anxious in anticipation of loud relative to Gaussian full-width-at-half-maximum 6 mm filter. Using the soft sounds. general linear model in SPM5, first-level single subject sta- Neural correlations with self-report anxious anticipa- tistical parameter maps were created from a model, which tion states. Participants’ trial-by-trial self-reported anxiety specified both blocks of anticipation (aversive and neutral; ratings was included as regressors in the first-level SPMs. cue þ countdown: 17 s) and auditory events (aversive and Contrast files for these regressors were then used at the neutral; 0 s). Bilateral amygdala and insula masks were cre- second-level to assess whether anticipatory reactivity in our ated using the Masks for Regions of Interest Analysis soft- ROIs was associated with individuals’ subjective experience ware (Walter et al., 2003). Region of interest (ROI) analyses of anxious anticipation. As displayed in Figure 2, the right were preformed using a false discovery rate search volume anterior insula was positively associated with participants’ corrected ¼ 0.05 with an extent threshold¼ 10 continuous self-reported anxiety during both aversive and neutral voxels. trials. On the other hand, the amygdala bilaterally covaried to a greater extent with participants’ self-report anxiety RESULTS during aversive compared to neutral anticipation (see Analyses of participants’ self-reported anticipatory Table 1). Thus, the right anterior insula was associated the anxiety subjective experience of anxious anticipation during both These analyses only included the 23 individuals who com- high- and low-anxiety inducing trials, whereas the amygdala pleted the version of the task with self-reported feedback of was selectively associated with feelings of anxiety during anxious anticipation. highly aversive trials. The feeling of anxious anticipation SCAN (2011) 77 Analyses of aversive auditory anticipation (Figure 3a). Time-series data were extracted for each condi- tion from the active voxels within right amygdala and insula. These analyses include all 35 individuals who completed The data were linearly interpolated, detrended and then either version of the auditory anticipation task. averaged across voxels and trials for each participant. As Aversive auditory anticipation-related activity. An aver- can be seen in Figure 3b, the amygdala and insula responded sive vs neutral anticipation second-level t-test contrast was in a similar fashion where activation was increased in aver- created to assess the neural correlates of aversive auditory sive relative to neutral trials 6 s and sustained throughout anticipation. These ROI analyses revealed that the right the period of anxious anticipation. An additional whole amygdala and bilateral insula were more active during brain analysis of aversive vs neutral anticipation with a periods of aversive compared to neutral anticipation false discovery rate corrected ¼ 0.05 and an extent thresh- old¼ 20 continuous voxels was used for further exploration. X & O Ratings X > O Ratings In addition to the insula and amygdala, a number of other z = –2 y = –2 structures including the left dorsolateral prefrontal cortex Insula (DLPFC), bilateral brainstem/inferior colliculus, medial superior frontal gyrus, and left cerebellum all displayed increased activation during aversive compared to neutral auditory anticipation (see Table 1 for details). Amygdala 2 Correlations with trait anxiety. Trait anxiety was included as a covariate in the ROI analyses to assess the extent to which this variable predicted activity in the amyg- LR dala and insula during the anticipation of aversive sounds. As shown in Figure 4a, trait anxiety was positively associated Fig. 2 Displayed on the left is activity in the right anterior insula that was predictive with anxious anticipatory activation in the left amygdala. At of intertrial differences in participants’ self-reported level of anxious anticipation a reduced threshold of P < 0.005, the left insula was during both aversive and neutral anticipation trials. The amygdala (right panel) uncorrected was bilaterally positively associated with participants’ ratings of anxious anticipation positively associated with trait anxiety. Extracted activity during aversive compared to neutral trials. Activation displayed at P < 0.005 uncorrected from these clusters was linearly interpolated, detrended for illustrative purposes. and then averaged across voxels and trials for each Table 1 Aversive auditory anticiption-related activity MNI Coordinates Maximally activated voxel Analysis and region Hemisphere xyz Voxels t-value P-value Aversive > Neutral anticipation (ROI) Amygdala R 18 2 18 19 4.30 <0.05 SVC Insula L 44 14 4 62 5.57 <0.05 SVC R40 18 8 98 5.13 <0.05 SVC Aversive > neutral anticipation (whole brain) Brainstem/inferior colliculus L 10 32 12 24 5.69 <0.05 FDR R14 28 12 51 5.24 Insula L 44 20 6 163 5.65 <0.05 FDR R40 18 8 42 5.13 <0.05 FDR Amygdala R 16 4 20 23 5.13 <0.05 FDR Superior frontal gyrus L–R 4 8 56 51 5.31 <0.05 FDR Dorsolateral prefrontal cortex L 30 46 28 20 4.52 <0.05 FDR Cerebellum L 22 66 18 50 4.92 <0.05 FDR Trait anxiety (ROI) Amygdala L 30 2 26 31 4.27 <0.05 SVC Insula L 42 16 0 26 3.70 <0.005 uncor X and O ratings (ROI) Insula R 38 12 16 66 4.28 <0.05 SVC X > O ratings (ROI) Amygdala L 24 2 14 23 4.18 <0.05 SVC R26 0 14 28 4.21 <0.05 SVC t-value 78 SCAN (2011) J. M.Carlson et al. Anxious > Neutral Anticipation Covariation with Trait Anxiety (a) (a) z = –8 y = –2 z = –3 y = –2 Insula Insula Amygdala Amygdala L R L R Anxious 2 2 Early (b) (b) 60 Neutral Mid 1 1 Late 0 0 −1 −1 40 40 −2 −2 4 8 12 16 4 8 12 16 Time (sec) Time (sec) 20 20 -4 0 4 8 -5 0 5 10 Fig. 3 (a) The bilateral insula (upper left panel) and right amygdala (upper right panel) were activated across participants during the anxious anticipation of a loud Insula Activation Amygdala Activation sound. Activation displayed at P < 0.001 for illustrative purposes. (b) The uncorrected time-series data indicate an elevated response within both the right insula (lower left Fig. 4 (a) Anxious anticipation-related activity within the left anterior insula (upper panel) and amygdala (lower right panel) during anxious relative to neutral antici- left panel) and amygdala (upper right panel) were sensitive to individual differences pation that begins 6 s post cue and sustains throughout the countdown. in trait anxiety. Individuals with higher levels of anxiety also had higher levels of activation in the left anterior insula and amygdala during aversive relative to neutral anticipation trials. Activation displayed at P < 0.005 for illustrative purposes. uncorrected (b) Trait anxiety was significantly correlated with insula (lower left panel) reactivity participant. The first 2 s of these interpolated time-series during the late (r¼ 0.36, P < 0.05), but not early (r¼0.13, P > 0.1) or middle (r¼ 0.18, P > 0.1), phases of aversive anticipation. Amygdala (lower right panel) were discarded, while the remaining 15 s was split into activity correlated with trait anxiety during the middle (r¼ 0.39, P < 0.05) and late early (3–7 s), middle (8–12 s) and late (13–17 s) phases of (r¼ 0.35, P < 0.05), but not early (r¼ 0.24, P > 0.1) phases of anticipation. anticipation. Trait anxiety was positively correlated with left amygdala activity during the middle (r¼ 0.39, P < 0.05) and late (r¼ 0.35, P < 0.05) phases of anticipation. The left anticipation. Furthermore, activation in the amygdala and insula positively correlated with trait anxiety during the late insula is predictive of an individual’s feeling state of (r¼ 0.36, P < 0.05), but not middle (r¼ 0.17, P > 0.1), phase anxious anticipation. of anticipation (see Figure 4b). Neither structure was asso- ciated with trait anxiety for the early phase of anticipation Role of the amygdala and insula in feeling (amygdala: r¼ 0.24, P > 0.1, insula: r¼0.13, P > 0.1). anticipatory anxiety The right anterior insula was sensitive to variability in DISCUSSION individuals’ anxious feelings during anticipation which is Participants’ feelings of anxiety were positively associated consistent with its proposed role in conscious awareness of with activation in the right anterior insula during anticipa- one’s own feeling states (Craig, 2003; Critchley et al., 2004). tion of both aversive and neutral sounds. Conversely, acti- Unlike the insula, amygdala activity was only associated with vation in the amygdala positively covaried with anxious variability in individual’s feeling states during anxious (rela- feelings, but only during anxious anticipation (Figure 2). tive to neutral) anticipation. That is, the degree to which an In addition, the right amygdala and bilateral insula were individual’s amygdala response was predictive of their generally activated during periods of anxious auditory antic- self-reported level of anxious anticipation was restricted to ipation (Figure 3). Anxious anticipation-related activation the aversive/loud sound trials. Given that the amygdala is of the left amygdala and insula were positively associated known to elicit and modulate physiological responses to with individual differences in trait anxiety (Figure 4). threat (Davis and Whalen, 2001; LeDoux, 1996) and that These findings suggest that across individuals there is an physiological responses contribute to one’s feeling state amygdalo-insular network for the anticipation of negative (Craig, 2003), the amygdala may play an indirect role in events and that activity within this network is relatively ele- modulating individuals’ feeling states in highly arousing vated in highly anxious individuals during aversive auditory circumstances. Indeed, models of amygdala functionality Mean Intensity t-value Trait Anxiety t -value The feeling of anxious anticipation SCAN (2011) 79 (Davis and Whalen, 2001; LeDoux, 1996) do not view this undesirable event. Indeed, another fMRI study of aversive structure as the neural substrate underlying the subjective anticipation utilizing the countdown methodology also did experience of emotion (or even specifically fear). On the not report activations in the anterior cingulate (Phelps et al., other hand, the anterior insula was predictive of participants’ 2001). Previous research indicates that the ACC is involved feeling states in both low and high arousal conditions, which in conflict monitoring and the processing of expectations suggests that activation in the insula is more generally pre- (Botvinick, 2007; Sallet et al., 2007). In anticipation para- dictive of one’s internal feelings. Taken together the findings digms the ACC may play a similar role where the ACC ‘mon- in this study and previous research (Craig, 2003; Critchley itors’ ones expectations about the temporal proximity of the et al., 2004) suggest a general role of the insula in the pro- anticipated aversive event. However, future research that cessing and representation of one’s internal feeling state, directly manipulates temporal certainty is needed to test while the amygdala may play a more specific role in contri- this speculative role of the ACC. buting to anxious worry states by modulating physiological In addition to the amygdala and insula, the left DLPFC, responding under conditions of high arousal. bilateral brainstem/inferior colliculus, medial superior fron- tal gyrus and left cerebellum were all activated during anx- ious auditory anticipation. The extent to which each Neural correlates of aversive auditory anticipation component of this anticipatory system is involved in differ- To the best of our knowledge, the current findings provide ent anticipatory situations is unknown. Although it is the first evidence that the right amygdala and bilateral insula unclear whether the BOLD signal reflects local inhibitory are activated during periods of anxious auditory anticipa- or excitatory neuronal activity, it may be expected that in tion. The finding of anticipatory insula reactivity to an aver- anticipation of a loud sound a general dampening or gating sive auditory stimulus, which was neither disgusting nor of auditory processing would be adaptive. Consistent with painful, suggests that the role of the insula in aversive antic- this notion, we found that activity in the inferior colliculus ipation is not that of a specific preparatory response to dis- was modulated by aversive auditory anticipation, which may gust or pain. Rather, our findings suggest that the role of the represent subcortical gating of auditory processing. The insula in aversive anticipation appears to be more consistent DLPFC activation is consistent with previous findings of with its previously implicated role in mediating interoceptive anticipatory PFC activations (Simpson et al., 2001; representations (Craig, 2003) and conscious affective feeling Simmons et al., 2004, 2006; Nitschke et al., 2006; Straube states (Critchley et al., 2004). On the other hand, the amyg- et al., 2007; Onoda et al., 2008). Activation in this region is dala is known to be sensitive to a variety of threatening also implicated in cognitive reappraisal (Ochsner et al., stimuli including social (Morris et al., 1996) and fear con- 2002) and may indicate an unsolicited attempt of partici- ditioned (Knight et al., 2005) cues. The amygdala response pants to regulate their anticipatory response. Thus, similar to to potential threat appears to rely upon limited sensory other sensory modalities, aversive auditory anticipation information (Morris et al., 1998; Whalen et al., 1998; recruits a distributed network of brain structures including Pasley et al., 2004; Williams et al., 2004) and results in a the amygdala, insula, and DLPFC among others, but also rapid modulation of physiology (Morris et al., 1998) and recruits auditory specific structures such as the inferior attention-related behavior including modulations of sensory colliculus. cortex (Carlson et al., 2009). Given the characteristics of the amygdala and insula as well as the similar time course of the Association with trait anxiety anxious anticipation-related reactivity in these structures (see Figure 3b), we speculate that these two affective pro- Anxious anticipation-related activation of the left amygdala cesses may occur in parallel. That is, during periods of anx- and insula were positively associated with individual differ- ious anticipation the amygdala may detect threat cues and ences in trait anxiety. Although anxiety-amygdala associa- initiate the fear response including modulations in physiol- tions have been observed in paradigms designed to elicit automatic responses (Rauch et al., 2000; Etkin et al., 2004; ogy and attention. At the same time (at least at the temporal Armony et al., 2005; Bryant et al., 2008), these associations resolution of fMRI), visceral changes associated with this have also been reported in anticipation paradigms response are represented within the insula and contribute to an anxious feeling state of aversive anticipation, which (Lorberbaum et al., 2004). Previous research has also indi- may in turn modulate processing in the amygdala. cated that the insula is elevated in high anxiety individuals Surprisingly, we did not find activation in the anterior during aversive anticipation (Lorberbaum et al., 2004; cingulate cortex (ACC), a region which has previously Simmons et al., 2006; Straube et al., 2007). Thus, the been shown to be activated during aversive anticipation observed anxiety associations in the amygdala and insula (Nitschke et al., 2006; Straube et al., 2007; Onoda et al., during aversive anticipation are consistent with previous 2008). This may be due to the methodology we employed findings and indicate an elevated anticipatory response in to assess anxious auditory anticipation. In particular, the anxiety. Here, we add to this literature with our finding of countdown in our study may have reduced or eliminated an elevated amygdala response in highly trait anxious indi- the temporal uncertainty associated with the anticipated viduals that starts in the middle and is maintained into the 80 SCAN (2011) J. M.Carlson et al. Dalton, K.M., Kalin, N.H., Grist, T.M., Davidson, R.J. (2005). Neural-car- late phase of aversive anticipation. In contrast, insula reac- diac coupling in threat-evoked anxiety. Journal of Cognitive Neuroscience, tivity was only associated with trait anxiety during the late 17(6), 969–80. phase of anticipation. These results indicate that in highly Davis, M., Whalen, P.J. (2001). The amygdala: vigilance and emotion. anxious individuals there is a relatively early sustained amyg- Molecular Psychiatry, 6(1), 13–34. dala sensitivity to anticipated threat that is accompanied by a Etkin, A., Klemenhagen, K.C., Dudman, J.T., Rogan, M.T., Hen, R., Kandel, E.R., et al. (2004). 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Journal

Social Cognitive and Affective Neuroscience – Oxford University Press

Published: Jan 5, 2011

Keywords: amygdala insula anxiety anticipation auditory

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