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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Depress Anxiety. Author manuscript; available in PMC Dec 1, 2011.
Published in final edited form as:
PMCID: PMC3010373

Anxiety sensitivity correlates with two indices of right anterior insula structure in specific animal phobia

Isabelle M. Rosso, Ph.D.,1,2 Nikos Makris, M.D., Ph.D.,2,4 Jennifer C. Britton, Ph.D.,5 Lauren M. Price, B.A.,1 Andrea L. Gold, M.S.,6 David Zai, B.A.,3 John Bruyere, B.A.,3 Thilo Deckersbach, Ph.D.,2,4 William D. S. Killgore, Ph.D.,1,2 and Scott L. Rauch, M.D.1,2



Anxiety sensitivity (AS) is a dispositional trait involving fear of anxiety-related symptoms. Functional imaging research suggests that activity of the anterior insular cortex, particularly the right insula, may both mediate AS and play a role in the pathophysiology of phobias. However, no imaging studies have examined whether AS relates to insula morphology. We examined whether AS was significantly correlated with right anterior insula volume and thickness among adults with specific animal phobia (SAP) and healthy comparison (HC) subjects.


Nineteen adults with SAP and 20 demographically group-matched HC subjects underwent magnetic resonance imaging (MRI) at 3 Tesla. Subjects also completed the Anxiety Sensitivity Index (ASI). Regression and correlation analyses examined ASI scores in relation to anterior and posterior insular cortex volume and thickness within and across subject groups.


SAP subjects had significantly higher ASI scores than HC, but did not differ in terms of insula volumes or thickness. ASI scores predicted right anterior insula thickness in SAP but not HC subjects, and right anterior insula volume in the sample as a whole. Correlations of ASI scores with left anterior and posterior insula volume and thickness were not significant in either group.


These findings suggest that right anterior insular cortex size is a neural substrate of AS within specific phobia, rather than an independent diagnostic marker of the disorder. Future investigations should examine whether heightened AS represents a shared intermediate phenotype across anxiety disorders, manifesting functionally as increased insular reactivity and clinically as a fear of anxiety symptoms.

Keywords: phobic disorders, anxiety sensitivity, magnetic resonance imaging, insular cortex, anxiety, fear


Anxiety sensitivity (AS) is a dispositional trait characterized by a proneness to anxiety due to a `fear of anxiety'.[1] This fear results from beliefs that anxiety is dangerous and will result in catastrophic consequences, such as mental illness, loss of control, heart attacks, embarrassment, or intolerable negative emotion.[2] Because of these beliefs, individuals with high AS are hyper-alert to interoceptive symptoms of anxiety, worry in advance about becoming anxious, and attempt to avoid anxiety-provoking stimuli.[2, 3] Although most often studied in relation to panic disorder, heightened AS has been found to varying degrees across most if not all anxiety disorders, including specific phobia.[4, 5] This finding is not surprising given that excessive danger prediction and avoidance are cardinal and shared features of all anxiety disorders. In the case of phobias, individuals who cross the diagnostic threshold are hypervigilant to the possibility of exposure to the phobogenic stimulus and actively avoid it in their daily lives. When exposed to the feared stimulus, people with phobias exhibit a rapid and exaggerated somatic response, including increased heart rate, blood pressure and exaggerated startle.[6] The nature and magnitude of this fear response suggests that it is mediated by a potentiation of the brain's fear network.

The insular cortex, particularly the anterior insula, is a key component of fear circuitry[7] and has been proposed as a neural mediator of AS.[8] Some have proposed that the anterior insula is particularly involved in the anticipation of undesirable events,[810] including the prediction of future aversive emotional states that have been associated with conditioned stimuli.[8] Anterior insula activation has been demonstrated during the anticipation and experiencing of aversive bodily states and negative emotions, and the degree of activation correlates with AS and other measures of anxiety proneness in healthy subjects.[1113] The right anterior insula appears especially important for conscious awareness of interoceptive states; specifically, it has been proposed that the right anterior insula integrates bodily cues and external sensory information into subjective feelings.[14, 15] A study by Critchley and colleagues[15] found that both functional activity and physical size of the right anterior insula were positively correlated with healthy subjects' ability to perceive their own heart beat, an indicator of interoceptive sensitivity that overlaps with the construct of AS.[16] In contrast with the anterior insula's role in mediating emotional and homeostatic states, the posterior insula appears more strongly associated with visual, motor and somatosensory functions.[15]

Anterior insula function has also been consistently associated with the processing of phobia-relevant stimuli. Compared with healthy individuals, animal phobics have shown increased neural activity of the anterior insular cortex during the anticipation and processing of phobogenic stimuli.[6, 15, 1726] Interestingly, some have found that enhanced insula activation is especially pronounced and even selective to phobia-relevant stimuli, rather than generalized across all fear-inducing stimuli.[6, 21] A selectively abnormal insula response to phobic material is consistent with the phenomenology of the disorder, and may argue against an anatomical defect. However, insula morphology has yet to be formally examined in specific phobia.

In this study, we examined AS and two MRI structural indices of insular size – cortical gray matter volume and thickness – in a sample of adults with and without specific animal phobia (SAP). Based on the research discussed above, we expected that SAP subjects would have higher AS than HC subjects, and we had no à priori hypotheses about group differences in insular morphology. We hypothesized that AS would be positively associated with right anterior insula volumes and thickness in healthy and SAP subjects, and that these correlations would be significantly larger in the phobic subjects who, by definition, are more anxiety-prone. We did not expect AS to predict left anterior or posterior insula morphology.



We studied 19 SAP subjects with a phobia of small animals (i.e., rodents, snakes, and/or spiders), and 20 healthy comparison (HC) subjects. Subjects were selected as part of an NIMH-funded study (PI: Rauch) utilizing structural and functional neuroimaging. Subjects were recruited via advertisements in the local community and provided written informed consent after a full explanation of study procedures. Each subject was then assessed using the Structured Clinical Interview for DSM-IV-TR – Patient Version (SCID-I/P)[27] to ensure that SAP subjects met DSM-IV criteria for current specific phobia, animal type, and that HC subjects had no history of Axis I pathology. SAP subjects had an average duration of illness of 22 ± 8 years, meaning that most patients dated the beginning of their phobia in early childhood. Participants were excluded if they met criteria for current or past Axis I diagnoses other than SAP. All participants were free of psychotropic medications for at least 4 weeks prior to the time of study participation, and were free of known medical or neurologic conditions that could affect brain structure. In addition, subjects were excluded if they had any MRI contraindications (e.g., metal implants, or claustrophobia). A nominal financial compensation was provided for participation. All study procedures were approved by the Massachusetts General Hospital (MGH) and McLean Hospital Institutional Review Boards.

Anxiety Sensitivity Index

Participants completed the 16-item Anxiety Sensitivity Index (ASI).[2] The ASI assesses the degree to which one is afraid of anxiety symptoms due to beliefs that anxiety will have negative psychological (e.g., “It scares me when I am unable to keep my mind on a task”), physiological (e.g., “It scares me when my heart beats rapidly”), or social (e.g., “It is important to me to not appear nervous”) consequences. Each item is scored from 0 to 4 and the scale has been validated as a reliable and specific measure of anxiety sensitivity, distinct from what is measured by scales of anxiety per se.[2, 28, 29]

MRI Procedures

Whole brain MR images were acquired on a 3.0 Tesla Siemens Trio whole body scanner equipped with a 12-channel head coil or a quadrature RF head coil at one of two locations (Massachusetts General Hospital, n = 22, McLean Hospital, n = 17). A sagittal localizer scan preceded a coronal T2-weighted sequence to rule out clinical neuropathology. Two sagittal 3D magnetization-prepared-rapid-acquisition-gradient-echo (MP-RAGE; T1-weighted, non-selective inversion-prepared spoiled gradient echo pulse) sequences were collected for morphometric analyses: TR/TE/T1/flip = 2.53 s/3.39 ms/1.1 s/7, bandwidth = 190 Hz/pixel, sampling matrix = 256 × 192 pixels, field of view = 256 × 256 mm2, effective slice thickness = 1.33 mm on a 170 mm slab of 128 contiguous slices. Structural scans were transferred to the MGH Center for Morphometric Analysis (CMA) and coded for blind image analysis.

MRI-Based Segmentation

Segmentation was performed with double blinding to group category and study hypotheses by trained technicians at the CMA. The cerebrum was analyzed on coronal images utilizing a semi-automated technique with Cardviews software,[30, 31] and segmented into gray and white matter tissue types. Specifically, the cortical ribbon was defined by two outlines, one external outline between the subarachnoid CSF and the cerebral cortex, and the other between the cerebral cortex and underlying cerebral white matter.[31, 32]

Cortical Parcellation & Thickness

The segmented volumes of the cerebrum were converted into inflated three-dimensional “surface” representations of the cortex in FreeSurfer,[33] in preparation for manual delineation. Each subject's surface representation of the cortex was then manually parcellated using a tool that is an extension of the Freesurfer environment, implemented by the TkMedit and TkSurfer programs. Specifically, the cortical surface was subdivided into 55 parcellation units (PUs) by hand-tracing major anatomical boundaries (sulci, fissures, gyri, planes) using criteria previously described.[34, 35] The insula is one of these PUs and has excellent average ICC's for both intraand inter-rater reliabilities, varying from .84 to .92.[35] In addition, the insula was subdivided into its anterior and posterior insular lobules[36] by tracing the central sulcus of the insula (Figure 1). The central sulcus of the insula represents the inferior border of the anterior insula and the superior border of the posterior insula.[36] Cortical thickness was computed using Freesurfer as previously published.[32]

Figure 1
Surface assisted parcellation.[33] A) Major cortical sulci and fissures are delineated manually (insula sulcus (ins) shown as thick pink line; central sulcus of the insula (cesi) shown as thick purple line that divides the insular cortex into anterior ...

Statistical Analyses

We compared SAP and HC subjects on ASI scores, intracranial volume (ICV), average cortical thickness, and unadjusted insula volumes and thickness using analysis of variance. Insula volumes were adjusted for total intracranial volume (ICV) in all subsequent analyses by using ratios of insula volume / ICV. We examined group differences in left and right insula volumes and thickness with the latter as dependent variables in general linear models (GLM), using group (SAP, HC), ASI score, and the interaction of group × ASI as independent variables. We tested the à priori hypotheses that ASI and group × ASI would significantly predict right anterior insula volume and thickness using an alpha of .05. For GLM models predicting left anterior and left/right posterior insula variables, we used a Bonferroni-adjusted alpha of .008. When significant group × ASI interactions emerged, we conducted follow-up Pearson correlations within each subject group. When only a significant main effect of ASI was found, we conducted a follow-up Pearson correlation within the whole sample. Cook's Distance score was used to exclude outlier data points.[37] An outlier was defined as Cook's Distance score larger than 3 standard deviations (SDs) above the mean Cook's D.This criterion resulted in zero to a maximum of two subjects excluded per GLM analysis. Significant correlations between ASI score and insula volume/thickness were followed by post hoc stepwise linear regressions to examine the variance in insula volume/thickness explained by potential covariates and confounds, namely age, sex, and scan site, as well as average cortical thickness for insula thickness analyses. These regressions entered ASI score and the afore-mentioned covariates using a stepwise mixed procedure with an entry probability of .05 and removal probability of .10. For all analyses, one-tailed tests were used for à priori hypotheses; otherwise, two-tailed tests were applied.


As shown in Table 1, the two groups were matched on demographic variables. ASI scores were significantly higher in SAP than HC subjects (Table 1; Cohen's d = 0.67). Table 2 shows means and standard deviations for whole brain and insula size measures, which did not differ between the groups.

Table 1
Subject group demographic characteristics and anxiety sensitivity (mean ± SD or N)
Table 2
Group mean and standard deviations for volumes (mL) and cortical thickness (mm)

GLM models predicting insula thickness and volumes

The GLM model predicting right anterior insula thickness showed nonsignificant main effects of group (F(1, 35) = 0.04, p = 0.84) and ASI score (F(1, 35) = 1.68, p = 0.20), and a significant group × ASI interaction (F(1, 35) = 4.66, p = .04). In follow-up Pearson correlation analyses, ASI score were significantly positively associated with right anterior insula thickness in SAP subjects (r = 0.57, df = 17, p = .01) but not HC subjects (r = −0.13, p = .60) (Figure 2a).

Figure 2
2A) Pearson correlations of right anterior insula thickness (mm) with anxiety sensitivity index (ASI) scores in adults with specific animal phobia (SAP) and healthy controls (HC); 2B) Pearson correlation of right anterior insula volume (mL) with ASI scores ...

In the model predicting right anterior insula volumes adjusted for ICV, there was a significant main effect of ASI (F(1,33) = 13.57, p = .0008) but not of group (F(1,33) = 2.42, p = .13), and the interaction of group × ASI was not significant (F(1,33) = 1.56, p = .22). In a follow-up Pearson correlation, ASI scores were significantly positively associated with right anterior insula volume (r = 0.47, df = 35, p = .003) within the whole sample (Figure 2b).

There were no significant main or interaction effects of group and ASI in the GLM models predicting left anterior insula volume or thickness, right posterior insula volume or thickness, and left posterior insula volume or thickness.

Hierarchical regressions

Based on the pattern of results above, stepwise linear regressions examined whether other variables accounted for the relationship of ASI scores with right anterior insula volumes in SAP and HC subjects combined, and with right anterior insula thickness in SAP subjects. In terms of right anterior insula volumes, only ASI score (β .47; t = 3.15; p = .003) contributed significantly to the model (R2 = 0.22; F[1,35] = 9.95; p = .003); age, sex, and scan site did not meet significance criteria for entry into the regression. Similarly, in the stepwise regression predicting right anterior insula thickness, only ASI score (β = 0.57; t = 2.87; p = .01) contributed significantly to the model (R2 = 0.33; F[1,17] = 8.25; p =.01); age, sex, scan site, and average cortical thickness did not enter the model as significant predictors. Moreover, duration of illness was not associated with any of the insula volume or thickness measures (p's > 0.55)


This study is first to report an association of anxiety sensitivity (AS) with anatomical measures of insula size in an anxiety disorder population. We found that adults with specific animal phobia (SAP) endorsed greater AS than healthy comparison (HC) subjects, and that higher AS predicted increased thickness of the right anterior insular cortex in the SAP group, as well as increased volume of the right anterior insula in the sample as a whole. The relationship of greater AS with insula morphology (thickness, volume) was specific to right anterior insula, and not significant for left anterior or posterior insula measures. Moreover, the associations of higher ASI scores with greater insula volume and thickness were not explained by differences in potentially confounding factors, namely age, sex, scan site, and whole brain scaling. Finally, volumes and thickness of anterior and posterior insula did not differ significantly between SAP and HC subjects. This pattern of results indicates that the volume of the right anterior insula correlates with ASI generally, and that the principal source of pertinent variance in SAP is thickness whereas another factor (e.g., surface area) may be the principal source of variance in HC. Overall, our findings are consistent with the hypothesis that the right anterior insula is a neural mediator of AS among individuals who are prone to excessive anxiety when exposed to feared (phobic) stimuli.

Increased cortical thickness and gray matter volume may reflect an increased number of structural and functional connections important for AS, possibly resulting from experience-induced neural plasticity of the right anterior insula. Numerous cross-sectional morphometric MRI studies have demonstrated that practice or experience with certain cognitive and motor skills is associated with greater cortical gray matter in relevant brain areas.[38] For example, navigational experience has been correlated with increased size of the posterior hippocampus[39] and musical ability with larger volume of motor and auditory brain regions.[40] Thus, one could reason that certain emotional propensities, such as AS, may have similar “experience-sensitive” neuroanatomical correlates. That is, a larger and thicker anterior insula may lead certain individuals to attend more readily to signs of anxiety and to develop high AS. Conversely, individuals with high AS, such as phobics who are sensitive to phobia-relevant stimuli, may engage the anterior insula more readily, leading to use-dependent gray matter increases in this region. The latter explanation is consistent with a parallel animal literature showing that early social enrichment in rodents leads to increased anxiety-like behavior along with higher neurotrophin levels and neurogenesis.[4143]

Variation in cortical thickness and volume detected with MRI could reflect a number of cellular events, including changes in the size, number, densities and pattern of arrangement of cells.[32] Given its macroscopic level of analysis, current 3 Tesla MRI technology cannot determine whether thicker and larger gray matter reflects increases in synaptic, glial, and/or capillary densities. Animal studies suggest that experience-induced increases in cortical gray matter result from a number of cellular morphological changes including the formation of new connections by dendritic branching and axonal remodeling.[38] Thus, the most parsimonious interpretation for our findings may be that an increased density of anterior insula circuitry occurs in response to upregulated use of this region by individuals who are hypervigilant for symptoms of anxiety or phobic reactions. That said, direct identification of morphological details within cortical gray matter awaits advances in imaging technology, such as promising developments in ultra-high field MRI (e.g., 7 Tesla).[44]

Our findings are consistent with growing evidence that the right anterior insula is involved in mediating subjective feelings. Functional imaging studies have shown that the anterior insula is activated bilaterally by stimuli that engender changes in a variety of homeostatic states, including temperature, pain, autonomic arousal, and a range of emotions.[14] Right anterior insula activity is also enhanced by explicit awareness of emotional responses, suggesting that it mediates the representation of bodily states as subjective feelings.[15, 45] Critchley and colleagues (2004) reported that activation of the right anterior insula during a heart rate detection task was intercorrelated with subjects' performance accuracy, as well as their subjective anxiety response during the task. In addition, gray matter volume of the right anterior insula predicted performance accuracy as well as a subjective measure of general visceral awareness.[15] Both the interoceptive measures used in the latter study and the ASI used in the current study tapped aspects of self-focused attention and sensitivity to signs of anxiety, supporting the role of individual differences in anxiety sensitivity or awareness mediated by the right anterior insular cortex.

The present findings may have implications for understanding shared behavioral and neural underpinnings of different anxiety disorders. Behavioral self-reports of heightened AS have been found across a range of anxiety conditions, including specific and social phobias,[2, 4] suggesting that AS may differ only in degree across different anxiety disorders. Consistent with the profile of a continuous variable that exhibits individual differences paralleling phenotypic differences, AS levels of phobic individuals are intermediate between those of healthy subjects and those of agoraphobia patients.[4] Similarly, anterior insula activation is increased during symptom provocation in many anxiety disorders,[4648] including specific phobia [e.g.,[6, 18, 21, 22, 2426]]. In addition, healthy individuals with anxious personality traits exhibit greater increases in anterior insula activation during the anticipation and processing of negatively-valenced stimuli than individuals without those traits.[13] Altogether, this suggests that shared anterior insula sensitivity across the anxiety disorders[8] may partly reflect a shared fear of and sensitivity to anxiety symptoms. It is possible that the effects of certain anxiety susceptibility genes that confer a general risk for anxiety disorders are mediated through anterior insular cortex structure, manifesting functionally as heightened AS and insula hyper-responsivity. The serotonin transporter gene (5-HTTLPR) may be an interesting candidate, given evidence that variation in its genotype predicts AS among individuals with a history of childhood adversity (maltreatment).[49]

This investigation has a set of limitations to be considered with respect to its interpretation. The sample size was relatively small, which may have limited the detection of small effects. For instance, although we found no effect of sex in any of the analyses, sex differences in AS[50] and in specific phobia[51] have previously been documented, and a larger sample would allow examination of sex-moderated effects. The conclusions of this study are based on correlational analyses, which cannot determine causal relations between the variables studied. In addition, scanning was conducted at two different locations, which may have introduced error into the data. However, approximately half of each group was scanned at each location, such that any systematic effect of magnet site would have affected the same proportion of phobics and controls. Moreover, the observed findings were unchanged after controlling for scanner location statistically.


The results of this study are in line with the view that right anterior insular cortex size is a neural substrate of AS within specific phobia, rather than a diagnostic marker of the disorder itself. It is possible that heightened AS represents an intermediate phenotype along a shared pathophysiologic pathway of anxiety disorders, manifesting functionally as increased insular reactivity and clinically as a fear of anxiety symptoms. Further studies are needed to elucidate whether the neural correlates of AS are shared across anxiety disorders, possibly reflecting a severity gradient of anxiety phenotypes.


We thank the subjects who participated in this study, and all study staff.

The authors disclose the following financial relationships within the past 3 years: National Institute of Mental Health (NIMH) R01 MH070730 (SLR) and K01 MH06987 (IMR). JCB is supported by the Intramural Research Program of the National Institutes of Health and the NIMH. TD is supported by NIMH K23 MH074895 (TD) and also participates in other federally grants funded by NIH, NIA and NIMH. None of the authors have relevant financial interests in this manuscript.


The authors have no conflicts of interest relevant to the subject matter of this manuscript.


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