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. Author manuscript; available in PMC: 2014 Nov 30.
Published in final edited form as: Psychiatry Res. 2013 Aug 28;214(2):10.1016/j.pscychresns.2013.06.010. doi: 10.1016/j.pscychresns.2013.06.010

Greater anterior insula activation during anticipation of food images in women recovered from anorexia nervosa versus controls

Tyson Oberndorfer a,b, Alan Simmons a,c,d, Danyale McCurdy a, Irina Strigo a,c, Scott Matthews a,d,e, Tony Yang a, Zoe Irvine a, Walter Kaye a,*
PMCID: PMC3880160  NIHMSID: NIHMS524549  PMID: 23993362

Abstract

Individuals with anorexia nervosa (AN) restrict food consumption and become severely emaciated. Eating food, even thinking of eating food, is often associated with heightened anxiety. However, food cue anticipation in AN is poorly understood. Fourteen women recovered from AN and 12 matched healthy control women performed an anticipation task viewing images of food and object images during functional magnetic resonance imaging. Comparing anticipation of food versus object images between control women and recovered AN groups showed significant interaction only in the right ventral anterior insula, with greater activation in recovered AN anticipating food images. These data support the hypothesis of a disconnect between anticipating and experiencing food stimuli in recovered AN. Insula activation positively correlated with pleasantness ratings of palatable foods in control women, while no such relationship existed in recovered AN, which is further evidence of altered interoceptive function. Finally, these findings raise the possibility that enhanced anterior insula anticipatory response to food cues in recovered AN could contribute to exaggerated sensitivity and anxiety related to food and eating.

Keywords: Neuroimaging, fMRI, interoception

1. Introduction

Anorexia nervosa (AN) is a biologically-based disorder of unknown etiology characterized by an inability to maintain a normal body weight, intense fear of gaining weight despite being underweight, and disturbed body or shape perception (American Psychiatric Association 2000). Recent studies show that genetic heritability accounts for approximately 50–80% of the risk of developing AN (Bulik et al. 2006) and contributes to the neurobiological factors underlying this illness (Kaye et al. 2009). Such factors may contribute to premorbid traits, such as anxiety (Kaye et al. 2004), harm avoidance (Fassino et al. 2002), perfectionism (Friederich and Herzog 2011), obsessionality (Anderluh et al. 2003; Joos et al. 2011a), and interoceptive deficits (Lilenfeld et al. 2006), that place some individuals at risk for developing an eating disorder.

The hallmark of restricting-type AN is pathological feeding behavior, namely severe and chronic reduction of food consumption. The advent of functional magnetic resonance imaging (fMRI) has allowed investigators to explore how alterations of brain function may contribute to abnormal eating behaviors in AN. Most functional MRI (fMRI) studies to date have examined the response to presentation of pictures of food in ill (underweight) AN participants compared to healthy controls. For example, an early fMRI study found elevated left insula blood oxygenation level dependent (BOLD) response when viewing images of low calorie versus high calorie drinks (Ellison et al. 1998). Uher et al. (Uher et al. 2003; Uher et al. 2004) found that ill AN showed greater activity in frontal and limbic regions, along with decreased activity in the inferior parietal lobule (IPL), when viewing pictures of food. Several studies (Santel et al. 2006; Gizewski et al. 2010) examined response in AN subjects to food pictures in both hungry and satiated states, which together show substantial variability in their findings but grossly implicate limbic and cognitive regions known to be involved in the visual processing of food stimuli (van der Lann et al. 2011).

Recent studies in obesity (Stice et al. 2008) have shown that it is important to investigate the anticipatory response to food. For example, animal studies show that dopaminergic neurons shift firing from the consumption of food to the anticipated consumption of food after conditioning, wherein cues associated with food consumption begin to elicit anticipatory food reward. Because AN have altered dopamine function (Frank et al. 2005), which is highly correlated with anxiety (Bailer et al. 2012), it is possible that they have an aberrant anticipatory response to cues. While a limited literature (Herpertz et al. 2008) suggests that AN have an aversive anticipation of palatable foods, to our knowledge, no studies have used imaging to investigate this crucial issue in AN.

High anxiety, particularly when dealing with food (Kaye et al. 2004; Steinglass et al. 2012), offers another reason to consider the influence of anticipation in AN participants. Dysregulated anticipation of future aversive events is a fundamental feature of anxiety spectrum disorders (Eysenck 1997). Anxious participants have shown enhanced activation in the right anterior insula and left dorsolateral prefrontal cortex (PFC) during the anticipation of aversive images (Simmons et al. 2010). Among healthy controls, anticipation of touch (Lovera et al. 2009) and anticipation of food pictures (Malik et al. 2011) have been found to activate the insula. While this activation is often greater in the stimulus condition, the group differences in affective regions are often more pronounced during the anticipatory phase (Simmons et al. 2006). The anterior insula has been identified as a region of interest in understanding disturbed appetite and interoceptive regulation in AN (Ellison et al. 1998; Kojima et al. 2005; Wagner et al. 2007 Nunn et al. 2008; Redgrave et al. 2008; Kaye et al. 2009).

The present study sought to determine whether individuals recovered from AN (RAN) have abnormal anticipatory response to viewing pictures of food. Recovered subjects were studied to avoid confounding effects of malnutrition and address possible trait characteristics of AN (see Supplemental Materials S1). We used the Uher pictures (Uher et al. 2003) to disentangle visual food stimuli anticipation and presentation in RAN compared to control women (CW). To accomplish this goal, a previously published image cueing task (Simmons et al. 2008) was modified to predict the presentation of food and object images. Previous studies of negative affective pictures in an anxious population (Simmons et al. 2006) and painful stimuli in a clinically depressed population (Strigo et al. 2008) have found greater insula activation during anticipation of negative stimuli, followed by a muted insula response upon presentation of the aversive stimuli. We hypothesized that RAN would display greater reactivity in anticipation of the salient food cues as evidenced by elevated anterior insula activation when compared to CW.

2. Methods

2.1. Participants

RAN participants and CW were recruited via flyers and electronic bulletin boards. Participants provided written informed consent and completed this cross-sectional study, which was approved by the University of California San Diego Human Research Protection Program. Trained doctoral level clinicians administered the Structured Clinical Interview for DSM-IV (First et al. 1997) and a psychiatric interview to determine eligibility and diagnosis. Fourteen RAN women (12 restricting type and 2 binging-purging type) were identified. When ill, RAN participants met criteria for DSM-IV diagnosis of AN, but never for bulimia nervosa. To be considered “recovered,” participants had to: 1) maintain a weight above 85% average body weight (Metropolitan Life Insurance Company 1959), 2) have regular menstrual cycles; and 3) have not binged, purged, or engaged in significant restrictive eating patterns for at least one year before the study. Twelve medically healthy CW, who had regular menstrual cycles since menses, were also identified. None of the CW met criteria for a current or lifetime diagnosis of an eating disorder or other Axis I disorder. Exclusion criteria for both groups included: 1) lifetime history of attention deficit hyperactivity disorder, psychotic or bipolar disorder; 2) current antidepressant or other psychiatric medication use, alcohol or substance abuse within 90 days of study participation; and 3) active medical problems or suicidal ideation.

2.2. Anticipation of food task

Participants performed a visual anticipatory task in which they viewed standardized images of food and non-food neutral valence object items (Uher et al. 2004) during fMRI. Participants were told that during the task a square would precede each food image and a circle would precede each object image; the task was faithful to these instructions. This allowed for measurement of brain activation during the period of anticipatory processing. Participants were asked to report the pleasantness/ unpleasantness ratings of the images immediately after the scan. A fixation cross appeared at the beginning of each trial (~8 seconds), followed by the square or circle “anticipation” stimulus (6 seconds), and the food or object image (2 seconds), for an average trial length of ~16 seconds (Figure 1). A total of 17 food and 17 object images were presented in a fixed pseudorandom order. During scanning, images were back-projected to the participants positioned inside the MRI scanner, at a visual angle of approximately 6°. Prior to scan, all participants received a standardized breakfast (bagel, cream cheese, banana, orange juice, skim milk: ~600 calories) with the instruction to “eat until feeling comfortably full.” Across groups, participants ate between 50-100% of the offered breakfast.

FIGURE 1. Task design.

FIGURE 1

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Anticipation paradigm based on a previously published cueing task (Peper et al. 2009) using images of food and object images obtained by Uher et al. (Uher et al. 2003).

2.3. Ratings task

Food and object images were rated on a scale of 1-10 for pleasantness (1 extremely unpleasant, 10 extremely pleasant) using a computerized rating program. Ratings were collected immediately after the scan and were averaged for each individual for both food and object responses. The averaged food-versus-object difference of pleasantness ratings was entered into a two-way analysis of variance (ANOVA) with anticipatory task condition (Food Anticipation, Object Anticipation) and group (CW, RAN) as factors. In addition, the average ratings for food and object images were correlated with anticipatory brain activations in all individuals.

2.4. Scan parameters

An event-related fMRI design was used. During the task, a fMRI run sensitive to BOLD contrast (Ogawa et al. 1990) was collected for each participant using a Signa EXCITE (GE Healthcare, Milwaukee) 3.0 T scanner (T2* weighted echo planar imaging, TR=2000 ms, TE=30 ms, FOV=230×230mm, 64×64 matrix, 33 2.6mm axial slices with a 1.4mm gap, 290 scans, 580 seconds). FMRI acquisitions were time-locked to the onset of the task. During the same experimental session, a T1-weighted image (MPRAGE, 172 sagittal slices, TR=8.0ms, TE=4.0ms, flip angle=12q, FOV=250×250, ~1mm3 voxels) was obtained for cross-registration of functional images.

2.5. Image analysis

Image processing and analysis was performed with the Analysis of Functional NeuroImages (AFNI) software package (Cox 1996). The preprocessed time series data for each individual were analyzed using a multiple regression model consisting of four task-related regressors of interest: 1) food anticipation trials; 2) object anticipation trials; 3) food image trials; and 4) object image trials. Five additional regressors were included in each model as nuisance regressors: three movement regressors to account for residual motion (roll, pitch, yaw), and regressors for baseline and linear trends to account for signal drifts. Percent signal change was calculated by dividing the fit for each regressor of interest by the residual baseline regressor. A Gaussian filter with a full width-half maximum of 6mm was applied to the voxel-wise percent signal change data to account for individual variation in the anatomical landmarks. Data from each participant were normalized to Talairach coordinates (Talairach and Tournoux 1988) and voxels were resampled to 4×4×4mm.

2.6. Task effects

To investigate brain activation during the food anticipation task, percent signal change for the anticipation phases (Food Anticipation, Object Anticipation, and Food Anticipation-Object Anticipation) were entered into whole brain voxel-based one-sample t-tests in both groups (RAN and CW). To investigate the brain activation during image viewing, percent signal change for the image phases was contrasted (Food Image-Object Image) in each group using a whole brain voxel-based two-sample t-test. Voxel thresholds were set at P<0.005. To control for multiple comparisons, Monte Carlo calculations were performed using the AFNI program AlphaSim (see Supplementary Materials S2), and it was determined that a minimum cluster volume of 1024mm3 was required to maintain significance.

2.7. Group effects

To investigate the group differences in brain activation during the food anticipation task, three separate analyses were performed. Percent signal change for the anticipation phases (Food Anticipation, Food Image, and Food Anticipation-Object Anticipation) were entered into the whole brain voxel-based two-sample t-tests in between groups (RAN versus CW). A similar group comparison was performed for the group contrast during the image phase (Food Image-Object Image). Because our primary goal was to examine group effects, we set a lower threshold for group comparisons. Voxel thresholds were set at P<0.05 for the single condition analysis (Food Anticipation and Object Anticipation) and image condition contrast (Food Image-Object Image) and at P<0.01 for the contrast analysis (Food Anticipation-Object Anticipation). AlphaSim was used to control for multiple comparisons, as described above.

2.8. Correlations with pleasantness ratings

RAN functional data during anticipation trials were correlated with trait characteristics, including perfectionism (Multi-dimensional Perfectionism Scale) (Frost et al. 1990), harm avoidance (Temperament and Character Inventory) (Cloninger et al. 1993), anxiety (State-Trait Anxiety Inventory-Version Y) (Spielberger et al. 1970), depression (Beck Depression Inventory-I) (Beck et al. 1961), and impulsivity (Barratt Impulsiveness Scale-11) (Barrett 1983). Alexithymia (Toronto Alexithymia Scale-20) (Bagby et al. 1994) was measured on the day of scan. Due to equipment failure, post-scan responses were not recorded in one CW and one RAN participant; thus, the pleasantness ratings analysis represents data from 11 CW and 13 RAN. Corrections were not made for multiple comparisons.

3. Results

3.1. Participant characteristics

RAN (n=14) and CW (n=12) were of similar ages and body mass index (Table 1). RAN scored significantly higher on overall perfectionism and harm avoidance compared to CW (Table 1). No group differences were observed for measures of depression, anxiety, impulsivity, or alexithymia (Table 1). Three RAN participants met criteria for current obsessive-compulsive disorder. Of those three participants, one presented with current and one with prior history of trichotillomania. Several RAN participants also met criteria for lifetime (but not current) anxiety and mood disorders such as social phobia (4 individuals), post-traumatic stress disorder (3 individuals), major depressive disorder (7 individuals), and generalized anxiety disorder (2 individuals). One RAN individual met criteria for past alcohol dependence.

TABLE 1.

Subject Demographics. Control women (CW) and women recovered from anorexia nervosa (RAN) groups were similar in age and current body mass index. Self-Assessments. RAN scored significantly higher for overall perfectionism and harm avoidance compared to CW. No group differences were observed for depression, anxiety, impulsivity, or total alexithymia. Beck Depression Inventory-I (BDI) (Beck et al. 1961). State-Trait Anxiety Inventory-Version Y (STAI-Y) (Spielberger et al. 1970). Barratt Impulsiveness Scale-11 (BIS-11) (Barrett 1983). Multi-dimensional Perfectionism Scale (MPS) (Frost et al. 1990). Temperament and Character Inventory (TCI) (Cloninger et al. 1993). Toronto Alexithymia Scale-20 (TAS-20) (Bagby et al. 1994). Pleasantness Ratings. Subjective pleasantness ratings of food (F(1,22)=1.070, P=0.312) and object (F(1,22)=0.112, P=0.741) images were similar between control women (CW, N=11) and women recovered from anorexia nervosa (RAN, N=13). Subjective pleasantness ratings of food images were significantly greater than object images for both CW (t(10)=3.748, P=0.004) and RAN (t(12)=2.427, P=0.032) groups.

CW RAN
Mean Std. Dev. Range Mean Std. Dev. Range P
Age 26.0 6.8 18-39 28.9 6.6 21-44 0.280
Body Mass Index 21.9 1.0 20-24 22.0 1.6 19-25 0.947
Age of Onset - - - 13.3 2.4 10-19 -
Disease Duration (Years) - - - 7.4 7.4 2-25 -
Years Recovered - - - 8.1 4.8 1-16 -
BDI: Depression 2.7 3.4 0-10 3.7 3.9 0-13 0.490
STAI-Y: State Anxiety 26.5 7.5 20-47 28.5 7.7 20-50 0.510
STAI-Y: Trait Anxiety 29.5 6.8 21-46 34.0 9.8 20-56 0.198
BIS-11: Motor Impulsivity 21.3 2.9 17-26 20.6 4.6 14-32 0.650
BIS-11: Attentional Impulsivity 13.3 3.0 11-20 13.8 4.9 9-25 0.794
BIS-11: Non-Planning Impulsivity 19.3 4.0 12-25 21.0 5.4 14-31 0.368
MPS: Overall Perfectionism 66.4 14.1 42-84 93.8 21.6 61-128 0.001
TCI: Harm Avoidance 7.7 2.9 2-13 14.5 7.6 3-27 0.008
TAS-20: Total Alexithymia 36.4 7.0 28-55 36.5 8.9 26-62 0.989
Food Pleasantness 5.1 1.7 2.3-7.4 4.4 1.5 2.0-6.8 0.312
Object Pleasantness 2.4 2.1 1.5-4.9 2.7 2.0 1.5-4.7 0.714
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3.2. Task performance

A between-subjects MANOVA with group and condition (food anticipation/object anticipation) was performed for both accuracy and reaction time on the continuous performance task. There were no significant group, task, or group by task effects (P>0.05).

3.3. Image ratings

A between-subjects MANOVA, using Wilks’ criterion (Λ) as the omnibus test statistic, was run to assess group differences on the post-scan images ratings. Using a Bonferroni correction for follow-up comparisons, CW and RAN groups (Table 1) were not significantly different in the post-scan pleasantness ratings for images of food, F(1,22)=1.070, P=0.312, images of objects, F(1,22)=0.112, P=0.741, or the difference between food and object pleasantness ratings, F(1,22)=0.86, P=0.772. Both the CW (t(10)=3.748, P=0.004) and RAN (t(12)=2.427, P=0.032) groups reported significantly higher pleasantness ratings for images of food versus objects.

3.4. Functional neuroimaging

3.4.1. Task effects

In a one-sample t-test, the RAN group activated the inferior frontal gyrus, occipital lobes, anterior and superior cinguate gyrus, and bilateral amygdalae, during object anticipation; they activated the right middle frontal gyrus, occipital lobes, and posterior cingulate gyrus during food anticipation. In contrast, the CW group activated the occipital lobes and left middle frontal gyrus during object anticipation, and during food anticipation, the occipital lobes and the left inferior frontal gyrus (Table 2). Lower pregenual ACC activation was observed in RAN versus CW when viewing images of objects versus food (Object Images>Food Images) (Volume: 2048mm3, XYZ=0,21,32). For CW, greater activation was found for RAN versus CW in the precuneus (Brodmann's area [BA] 7) in response to viewing food versus object images (Food Images>Object Images) (Volume: 1024mm3, XYZ=1,−71,40). For the comparison of viewing food and object images across groups, no significant clusters survived thresholding.

TABLE 2. Task Effects (P<0.005, minimum cluster volume 1024mm3).

Main effect regions of activation during anticipation of food and non-food visual stimuli are presented.

Group Condition mm3 # X Y Z Region of Interest BA
CW Food Anticipation 2752 43 35 −62 −8 R Fusiform Gyrus 37
1984 31 −41 −56 −7 L Occipital Lobe, Sub-Gyral WM
1664 26 −27 −80 −2 L Occipital Lobe, Sub-Gyral WM
1408 22 −43 35 10 L Inferior Frontal Gyrus 46
Object Anticipation 5120 80 34 −76 −5 R Inferior Occipital Gyrus 19
4544 71 −41 −54 −12 L Fusiform Gyrus 37
2752 43 −29 −82 −4 L Inferior Occipital Gyrus 19
1984 31 −44 21 23 L Middle Frontal Gyrus 46
RAN Food Anticipation 10176 159 −1 −48 39 Posterior Cingulate Gyrus 31
9536 149 −36 −69 −5 L Occipital Lobe, Sub-Gyral WM 19
3840 60 1 50 4 Medial Frontal Gyrus 10
3520 55 32 −81 0 R Middle Occipital Gyrus 18
1472 23 44 −52 −8 R Temporal Lobe, Sub-Gyral WM
1024 16 −25 −70 35 L Precuneus 7
1024 16 −25 −38 49 L Parietal Lobe, Sub-Gyral WM
Object Anticipation 8896 139 −39 −56 −10 L Fusiform Gyrus 37
3904 61 28 −43 −14 R Fusiform Gyrus 37
3712 58 43 −55 −8 R Occipital Lobe, Sub-Gyral WM
3264 51 31 −84 −2 R Occipital Lobe, Sub-Gyral WM
3072 48 43 31 11 R Inferior Frontal Gyrus 46
3008 47 47 8 26 R Inferior Frontal Gyrus 9
2880 45 25 −7 −13 R Amygdala
2368 37 −28 −88 −2 R Occipital Lobe, Sub-Gyral WM
2368 37 1 −30 28 Cingulate Gyrus
2304 36 −24 −5 −14 L Amygdala
1920 30 −1 −51 29 Anterior Cingulate Gyrus 32
1152 18 39 −13 47 R Precentral Gyrus 6
1088 17 −16 −21 64 L Precentral Gyrus 6
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CW: Control women. RAN: Women recovered from anorexia nervosa. Main effect regions of interest obtained in conditions viewing food or non-food images are not presented. Brodmann's area (BA). Talairach coordinates (X,Y,Z) (Talairach and Tournoux 1988). Volume (mm3). Number of voxels (#).

3.4.2. Group by task effects

During anticipation of food, RAN had greater activation than CW in the putamen, superior gyrus, and medial frontal (BA 10), while RAN had less activation than CW in the IPL (Figure 2, Table 3). When viewing images of food, RAN had greater activation than CW in the IPL, insula, and lateral orbitofrontal cortex and less activation in the medial temporal gyrus (Figure 3, Table 3). The between-group contrast for the activation difference between food anticipation and object anticipation (P<0.01) revealed one region of significant interaction in BA 13 of the right ventral anterior insula, F(1,25)=29.30, P<0.001 (Volume: 1344μL, XYZ=38,11,−8). This interaction was driven by greater insula activation in RAN versus CW while anticipating images of food, F(1,25)=16.33, P<0.001, and by deactivation of the insula in RAN while anticipating images of objects, F(1,25)=6.93, P=0.015 (Figure 4A,B). Two-tailed paired t-tests revealed that right anterior insula response to Food Anticipation versus Object Anticipation was significantly lower in CW, t(14)=−3.73, P=0.003, but greater in RAN, t(14)=3.91, P=0.002 (Figure 4B). No significant group-by-condition interactions were observed when comparing Food Images and Object Images. When the significance threshold was lowered to P<0.05, an additional region of interest was observed in the right medial dorsal nucleus of the thalamus (Volume: 2304μL, XYZ=−4,−16,11; data not shown).

FIGURE 2. Group Effects during Food Anticipation (P<0.05, minimum cluster volume 1024mm3).

FIGURE 2

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Axial images are displayed in Talairach Z coordinates (Talairach and Tournoux 1988). Control women (CW). Women recovered from anorexia nervosa (RAN).

TABLE 3. Group Effects (P<0.05, minimum cluster volume 1024mm3).

Activation differences between women recovered from anorexia (RAN) versus control women (CW) are presented for anticipation of food and viewing food images. Ordered by Talairach coordinates (X,Y,Z) (Talairach and Tournoux 1988), refer to Figure 3 and Figure 4 for images. Brodmann's area (BA). Volume (mm3). Number of voxels (#).

Condition mm3 # X Y Z Region of Interest BA Direction
Food Anticipation 1280 20 −16 31 −8 L Medial Frontal Gyrus 10 RAN>CW
1280 20 13 51 −2 R Superior Frontal Gyrus 10 RAN>CW
1344 21 28 −10 7 R Dorsal striatum, Putamen RAN>CW
2944 46 −3 −31 16 L Thalamus, Pulvinar RAN>CW
1664 26 −53 −32 37 L Inferior Parietal Lobule 40 CW>RAN
1536 24 14 15 41 R Medial Frontal Gyrus 32 RAN>CW
1088 17 15 33 36 R Medial Frontal Gyrus 8 RAN>CW
Food Images 1216 19 27 −67 −35 R Inferior Cerebellum CW>RAN
1088 17 −33 −73 −34 L Posterior Cerebellum RAN>CW
1344 21 2 −34 −21 Anterior Cerebellum RAN>CW
1344 21 −22 50 −16 L Superior Frontal Gyrus 11 RAN>CW
1600 25 −44 −49 9 L Superior Temporal Gyrus 39 CW>RAN
1408 22 −41 −49 9 L Superior Temporal Gyrus 39 RAN>CW
2304 64 39 −1 13 R Insula 13 RAN>CW
1216 19 −7 −31 18 L Posterior Cingulate Gyrus 23 RAN>CW
2432 38 41 −51 44 R Inferior Parietal Lobule 40 RAN>CW
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FIGURE 3. Group Effects during Food Images (P<0.05, minimum cluster volume 1024mm3).

FIGURE 3

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Axial images are displayed in Talairach Z coordinates (Talairach and Tournoux 1988). Control women (CW). Women recovered from anorexia nervosa (RAN).

FIGURE 4. Group (CW,RAN) by Condition (Food Anticipation, Object Anticipation) whole brain comparison.

FIGURE 4

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Regions of interest were thresholded at P<0.01 with a minimum cluster volume of 1024mm3. (A) One significant region of interest was identified in the right anterior inferior insula (1344mm3) characterized by (B) significantly increased response to anticipation of food, P=0.018, and significantly decreased response to anticipation of object images, P<0.001, in women recovered from anorexia nervosa (RAN) versus control women (CW). Post-hoc 2-tailed paired t-tests yielded significant within group and within condition differences. (C) The average difference of food and object pleasantness ratings showed a significant positive correlation with Food Anticipation – Object Anticipation percent signal change in this right anterior insula region in CW (r2=0.59) but not RAN (data not shown).

3.5. Behavioral-functional correlation

No significant correlations were observed with pleasantness ratings for either food or object images (XYZ=38,11,−8; Figure 4C). Greater insula activation in CW was significantly related (r2=0.59, P=0.03) to more positive pleasantness ratings, when calculated as the averaged difference between pleasantness of food and pleasantness of objects images. In contrast, there was no such relationship in RAN (r2=0.004). There were no significant correlations between insula activation and behavioral measures.

4. Discussion

This is the first neuroimaging study to investigate brain activation during the anticipation and viewing of food images versus object images in a group of individuals recovered from AN. This paper presents two major findings. First, compared to CW, RAN individuals showed greater activation of the right ventral anterior insula (Figure 4A) when anticipating food images versus object images (Figure 4B). Second, insula activation was significantly correlated with food pleasantness ratings in the CW group but not in the RAN group. In conjunction, these findings highlight the complex relationship, from both clinical and neurobiological perspectives, between food and food anticipation in anorexia nervosa.

4.1. Anticipatory activation in the anterior insula

During object anticipation, CW activation patterns were similar to those seen in other studies of anticipation in healthy populations, showing activation in the anterior insula (Adolphs et al. 2000; Samanez-Larkin et al. 2007). Importantly, in contrast to CW, RAN showed elevated anterior insula activation when anticipating food images but not object images (Figure 4). The ventral anterior insula is cytoarchitectonically closest to the limbic cortex and is extensively connected to other subcortical regions (Dupont et al. 2003), providing a link to socio-emotional function (Kurth et al. 2010). Importantly, the human gustatory cortex maps to the right anterior insula and bilateral central insula (Kurth et al. 2010) and serves as the primary taste cortex (Sanchez-Juan and Combarrors 2001; Small 2010). Other studies from our group found that insula activation during anticipation depends on stimulus intensity rather than valence (Simmons et al. 2008; Lovera et al. 2009). Pre-existing conditions are thought to create increased sensitivity to an impending arousing stimulus (Strigo et al. 2008). While speculative, it is possible that an enhanced anticipatory response to images of food in RAN could explain the exaggerated sensitivity of the anterior insula and the anxiety experienced with regard to their relationship to food. This interpretation matches the observed affective reactivity seen in AN to food-related stimuli (Brockmeyer et al. 2011; Steinglass et al. 2012). It should be emphasized that these data support a correlational relationship between insula dysfunction and the dissociation of anticipation versus experience of food in AN individuals, although a causal mechanism remains uncertain. It is important to note that greater activation in the insula during anticipation cues versus the viewing of food images does not necessarily imply that subjects are more responsive to the food image cue than the food image, rather, that the response to food images may be related to a dampened or multi-faceted response.

The anterior insula has been implicated in conditions of risk and uncertainty (Mohr et al. 2010) and is a primary region of interest in the pathophysiology of anxiety (Paulus and Stein 2006). Studies in anxiety and pain have found that the insula plays a key role in the anticipation of aversive stimuli (Ploghaus et al. 1999; Porro et al. 2002; Simmons et al. 2004; Simmons et al. 2006). It is well known that individuals with AN tend to be anxious (Kaye et al. 2004), and there is accumulating evidence that they have altered insula function (Ellison et al. 1998; Kojima et al. 2005; Wagner et al. 2007; Redgrave et al. 2008; Kaye et al. 2009).

We did not, however, find any relationship between baseline measures of trait or state anxiety and right insula activation. Moreover, there was no relationship to measures of depression or OCD. Thus, greater activity in the right ventral anterior insula among RAN individuals appears to be related to anticipation of the emotionally salient food stimuli and not to their baseline level of anxiety. This lack of a relationship between anxiety and insula activation in AN corresponds to a lack of correlation between insula activation and food image ratings in the current study.

4.2. Insula correlation with pleasantness

For most people, food is inherently pleasant. In fact, for CW, food-versus-object pleasantness ratings significantly correlated with anticipatory insula activation (XYZ=38,11,−8; Figure 4C). Similarly, other studies have found that healthy control subjects show a significant positive relationship between pleasure for tastes of food and insula activation (Spetter et al. 2010). While both control and RAN groups activate the anterior insula in response to pleasant tastes (Cowdrey et al. 2011), a relationship between activation and perceived pleasantness was notably absent in the RAN group (see Supplemental Materials S3). As seen previously (Cowdrey et al. 2011), the CW and RAN groups did not differ in subjective pleasantness ratings, suggesting that these findings were not related to diminished ratings in the RAN group. A previous study from our group (Wagner et al. 2007) found that for CW, pleasantness ratings for sweet taste were positively correlated with insula signal, whereas the RAN participants displayed no such relationship. RAN activation in the anterior insula is dissociated from self-report of the pleasantness of food and food stimuli.

4.3. Dissociation between anticipation and sensation in RAN

The response of RAN individuals to strong or salient interoceptive stimuli appears to be complex. Currently, only a few published studies are available to elucidate this mechanism. A separate study from our group (Strigo et al. 2013) assessing neural substrates of pain anticipation in RAN supports the unique role of the right anterior insula and anticipation of salient information within this population. Interestingly, when anticipating pain, RAN subjects also showed greater activation versus controls in the right anterior insula, as well as in the dorsolateral PFC (dlPFC) and cingulate. In contrast, when sensing pain, the RAN subjects showed greater activation versus controls within the dlPFC and decreased activation within the posterior insula. Similarly, prior studies from our group (Wagner et al. 2007; Oberndorfer et al. 2013) found that compared to controls RAN had diminished anterior insula response to tastes of sucrose.

Considered together, these studies of physiologically salient stimuli (food and pain) suggest that RAN demonstrate a mismatch between anticipatory and objective responses. Such a mismatch suggests altered integration that possibly leads to a disconnect between reported and actual interoceptive states. This proposed mechanism of anticipatory dissociation in the insula has been considered with regard to other psychiatric disorders. Specifically, the insula is thought to code interoceptive prediction error, signaling mismatch between actual and anticipated bodily arousal, which in turn elicits subjective anxiety and avoidance behavior (Paulus and Stein 2006). Along with interoceptive difficulties, this may also be tied to the preponderance of alexithymia in AN (Sexton et al. 1998), which also is related to increased insula activation and is thought to be tied to deficits in emotional processing (Heinzel et al. 2010). Future studies are needed to explore the role of insula dysregulation in AN symptomatology, specifically the discordance of anticipating versus experiencing salient stimuli, within the context of frontal and limbic circuitry.

4.4. Anticipation and emotion in AN

AN individuals tend to be obsessed with food and anticipating food, spending many hours per day counting calories, reading recipes, and cooking for others. Still, food is highly emotional (Brockmeyer et al. 2011) and associated with anxiety (Steinglass et al. 2012), and just the thought of food appears to generate substantial discomfort. Interestingly, Joos and colleagues (Joos et al. 2011b) showed that this emotional salience is reflected functionally by increased right amygdala activity in ill restricting-type AN viewing similar images of foods (Uher et al. 2003; Uher et al. 2004) The authors posited that pathologic thoughts and behaviors in AN individuals may be mediated by dysregulation of neural networks responsible for processing food stimuli of various modalities, which underlies exaggerated amygdala response. Our study did not observe similar amygdala response to food images. However, our cohort consisted of women recovered from AN who may not experience as profound an emotional response to food images as acutely ill AN subjects. It is also possible that the anticipation of viewing non-salient food images may have further diminished their emotional impact.

Given that food is an inherently emotional stimulus in AN, a mismatch between limbic hyperarousal and cognitive control may be tied to both interoceptive and emotional processing deficits in this recovered population. We observed right anterior insula hyperactivity in response to anticipating food images. It is worth noting that, similar to Joos et al., we did not observe differences of insula response in RAN individuals viewing food images. The present study adds to a growing literature that collectively suggests that dysregulation of insula function may contribute to disconnection between the approach and avoidance of food in AN.

4.5. Anticipation and reward error detection in RAN

Anticipation of an event may engage different neurocircuitry than detecting error of prediction (Knutson and Wimmer 2007), which may also be disturbed in AN individuals. Using a temporal difference model to test dopamine-related brain reward response to sweet tastes, Frank et al. (Frank et al. 2012) found that ill restricting-type AN individuals had increased right insula, striatal, and dlPFC response compared to controls during error detection. The insula findings described by Frank and colleagues are localized to BA 13 and lateralized to the right, similar to the present findings. As described above, this region of the insula is the primary taste cortex and is also involved in interoceptive processing. It is possible that exaggerated right anterior insula response during error detection may in fact be due to the sweet taste stimulus that informed subjects of a predictive error during this task. However, exaggerated insula response may also reflect aberrant error detection in AN individuals, suggesting the possibility of a shared role of the insula in processing anticipation and error detection. Taken together, AN individuals demonstrate exaggerated insula response to both anticipated and unexpected stimuli when compared to healthy control women.

4.6. Inferior parietal and medial prefrontal findings

In contrast to prior studies (Uher et al. 2003; Uher et al. 2004), we found significantly lower IPL activation during anticipation of food images, but greater IPL activation when RAN viewed images of food, compared with CW. Additionally, we found that food anticipation engaged the medial prefrontal inhibitory network significantly more in RAN compared to CW (Table 3), consistent with past studies in both RAN (Uher et al. 2003) and ill AN (Uher et al. 2003; Uher et al. 2004; Gizewski et al. 2010). These findings are discussed in greater detail in Supplementary Materials S4.

4.7. Comparison to prior studies with image presentation

The current study used the pictures of food developed by Uher (Uher et al. 2003). The Uher study, which compared nine RAN and nine CW (and 8 ill AN), differed in study design. Uher presented four sets of pictures: 1) food images, 2) color and shape matched object images, 3) emotionally aversive images, and 4) object images. Our study only used the first two sets of stimuli but also employed anticipatory cues directly preceding the food and object images. As discussed above, in prior research, arousing (specifically aversive) stimuli resulted in a greater activation prior to the stimulus, which led to subsequent decreased activation during the stimuli in affective (Strigo et al. 2008) or attentional (Simmons et al. 2006) regions. This reciprocal reaction during the stimulus that results from separating the cognitive preparation from the physical representation of the stimulus can obscure direct comparison of the stimulus phase. Thus, in light of the known dissociation of the affective impact from resultant behavior, and in the context of the proposed mechanism, the current study is in direct agreement with prior work.

Other studies examined ill AN individuals viewing food images in fasted and satiated states (Santel et al. 2006; Gizewski et al. 2010). When hungry, AN exhibited diminished activation in the right visual occipital cortex (Santel et al. 2006) and elevated activation in the PFC, postcentral cortex, and left anterior insula, relative to controls (Gizewski et al. 2010). When satiated, AN displayed greater activation in the left IPL (Santel et al. 2006) and the left insula (Gizewski et al. 2010) versus controls. Overall, these studies are consistent with the present findings of increased right anterior insula activation during anticipation of food images.

4.8. Limitations

In this study, we investigated a group of women recovered from AN. While metabolic problems complicate imaging in currently ill AN participants, the present RAN group findings are similar to findings in studies that examined currently ill AN patients (Uher et al. 2003; Uher et al. 2004), suggesting that a generalization is plausible. Also, anticipation of food stimuli has been compared to actual oral consumption of food in healthy (O'Doherty et al. 2002; Small et al. 2008) and obese (Stice and Spoor 2008) populations, but anticipation of visual food stimuli has not been assessed. It should be noted that the experience of a picture of food differs from the consumption of food, and comparisons using actual food stimuli should be addressed in future studies.

The current study also had several limitations of study design and analysis. The RAN group had a number of comorbid disorders. We lacked power to determine how these may have contributed to the current findings. Additionally, two of our 14 RAN participants were binge-purge subtype, which could potentially confound the results. These participants were kept in the sample to maintain power. While subjective pleasantness ratings were recorded, no data were collected regarding the potentially anxiety-provoking nature of the stimuli. As correction for multiple comparisons was not made in the exploratory correlation analysis, it is possible that the positive correlation observed between image pleasantness ratings and right anterior insula activity in CW may be due to chance.

Finally, with this anticipatory task, we expected to observe group and condition activation differences beyond the right anterior insula in regions that process anticipation and uncertainty. Group comparisons in fact yielded differences in the frontal cortex, right dorsal striatum, and thalamus (Table 3), though these group differences failed to reach significance in the group-by-task comparison. Larger group sizes will help elucidate activation differences in neurocircuitry related to anticipation.

4.9. Conclusion

We found that: (1) RAN women compared to CW showed greater activation of the anterior insula during anticipation of food versus object images, and (2) while anticipating the visual food cue, insula activation positively correlated with image pleasantness ratings in CW but not RAN. Anticipation of the food image was thus decoupled from the subjective experience of viewing food images in RAN individuals. These are novel findings in the anticipatory behavior and corresponding neural response of RAN individuals that together support the possibility of a dysregulation of interoceptive processing in AN.

Supplementary Material

01

Acknowledgements

Support by grants from National Institute of Mental Health (NIMH) MH46001 and MH42984, NIMH Training Grant T32-MH18399 and the Price Foundation. This work was supported by the Veterans Administration via Merit Grant (Alan N Simmons), Clinical Science R&D Career Development Award (Scott C Matthews) and the Center of Excellence in Stress and Mental Health (Alan N Simmons and Irina Strigo). The authors want to thank the functional magnetic resonance imaging (fMRI) staff for their invaluable contribution to this study and Eva Gerardi for the manuscript preparation. The authors are indebted to the participating subjects for their contribution of time and effort in support of this study.

Footnotes

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