Conceived and designed the experiments: SJB RU H-CF JT ICC. Performed the experiments: SJB H-CF. Analyzed the data: SJB OGO. Contributed reagents/materials/analysis tools: SJB OGO VG MB SCRW HBS JT ICC. Wrote the paper: SJB. Commented on the manuscript draft: OGO H-CF VG JT ICC. Helped in the recruitment of patients: JT ICC.
The authors have declared that no competing interests exist.
Previous fMRI studies show that women with eating disorders (ED) have differential neural activation to viewing food images. However, despite clinical differences in their responses to food, differential neural activation to thinking about eating food, between women with anorexia nervosa (AN) and bulimia nervosa (BN) is not known.
We compare 50 women (8 with BN, 18 with AN and 24 age-matched healthy controls [HC]) while they view food images during functional Magnetic Resonance Imaging (fMRI).
In response to food (vs non-food) images, women with BN showed greater neural activation in the visual cortex, right dorsolateral prefrontal cortex, right insular cortex and precentral gyrus, women with AN showed greater activation in the right dorsolateral prefrontal cortex, cerebellum and right precuneus. HC women activated the cerebellum, right insular cortex, right medial temporal lobe and left caudate. Direct comparisons revealed that compared to HC, the BN group showed relative deactivation in the bilateral superior temporal gyrus/insula, and visual cortex, and compared to AN had relative deactivation in the parietal lobe and dorsal posterior cingulate cortex, but greater activation in the caudate, superior temporal gyrus, right insula and supplementary motor area.
Women with AN and BN activate top-down cognitive control in response to food images, yet women with BN have increased activation in reward and somatosensory regions, which might impinge on cognitive control over food consumption and binge eating.
Bulimia Nervosa (BN) is defined by recurrent episodes of binge eating of large amounts of food, and compensatory measures to control for weight gain. (Diagnostic and Statistical Manual Fourth Edition,
Those with BN report an excessive urge to eat, coinciding with a sense of lack of control over their eating. This is in contrast to anorexia nervosa (AN), which is defined by emaciation and maintainance of less than eighty-five percent normal body weight via deliberate control of food intake and inhibition of appetite. However, women with both AN and BN report a fear of gaining weight and a desire to be thinner. These differences may manifest at the neural level as differential activation when thinking about eating food. People who binge-eat show altered prefrontal-cortical-striatal-insula responses to appetitive stimuli
The aim of this exploratory study, which uses a novel paradigm whereby eating-related cognitions are evoked by thinking about eating food shown in images, is to demonstrate a differential pattern of activation in cortico-striatal-insula regions between women currently ill with AN and BN. We hypothesize that: a) women with AN and BN compared to healthy controls (HC) have reduced striatal-insular cortex, and greater prefrontal cortical activation when thinking about eating food versus non-food items shown in images; b) women with BN have reduced prefrontal cortical activation but greater striatal-insular cortex responses in comparison to women with AN.
This study was approved by the South London and Maudsley (SLaM) NHS Trust Ethics Committee, study number: 297/02. Additionally, the study adhered to the guidelines as set out in the Declaration of Helsinki. Written informed consent was required from all participants, as approved by the SLaM ethics committee, and they were reimbursed for their participation.
50 right-handed females (aged 16–50 years) volunteered to participate in the study: 8 had a current DSM-IV diagnosis of bulimia nervosa (BN), 18 had a current diagnosis of anorexia nervosa (AN). Of these, 11 had a diagnosis of
72 colour photographs of high and low calorie, sweet and savoury food were presented on white plates on a blue background in random order: these were created by the authors. The control condition was 72 colour photographs of non-food items on white plates on a blue background (created by the authors, an example is found in the online supplement). Food and non-food items were selected and matched according to colour and visual structure. All images are available on request.
This is a 36-item measure of dysfunctional behaviour and cognitions related to eating, with sub-scales: eating concern, shape concern, weight concern and restrained eating, together with a global eating disorder score. Questions are scored between 0–6: higher scores indicate greater eating disorder pathology.
This is a 14-item self-report measure with 7 related to anxiety and 7 related to depression. Individual questions are scored on a 4-point scale: higher scores indicate greater anxiety or depression.
This structured interview is used for diagnosis, for general screening, and to obtain demographic information. Duration of illness is the time between diagnosis of AN and the time of the scan. It is noted that symptoms are most likely present before the formal diagnosis, but this measure gives a systematic score of illness duration.
Scanning was performed between 1.30 and 4 pm. Images were presented on a rear-projection screen and viewed through a double-mirror periscope attached to the headcoil. Images (food versus non-food) were presented during the same scanning period. An AB block-design of 6 blocks for the active (food images [A]) and 6 blocks for the control (non-food images [B]) conditions was used: blocks were alternated between active and control conditions. Each block consisted of 12 images: each was presented for 3 sec. with no gap, ie images for each category were presented continuously for 36 seconds. At the beginning of each block, a ‘partially silent’ period of 8 seconds, and another 8 sec. partial silent period at the end of each block (where no data was acquired and the Echo Planar Image [EPI] readout was disabled) was used to present audio stimuli/ obtain verbal responses. During these periods, slice selection, Radio Frequency (RF) and gradients continued, in order to maintain the MR signal in a steady state and to allow data collection to continue during subsequent volumes. Pre-recorded audio stimuli asked participants to a) imagine eating the food in the images, and b) imagine using the non food items. For each instruction, 4 separate but semantically similar phrases were given via headphones. In the second partially-silent period (at the end of each block), participants were asked to rate how anxious they felt on a scale of 0–10: participants reponded verbally. The duration of each block was 52 seconds (36 seconds of stimuli + two 8 second periods of ‘partial silence’), repeated 12 times (food versus non-food): total duration of the presentation of food versus non-food images was therefore 10.4 minutes.
The fMRI acquisition was performed on a GE Signa 1.5-Tesla scanner (GE Medical Systems, Milwaukee, Wisconsin). T2* -weighted images depicting Blood Oxygen Level Dependent (BOLD) contrast were acquired with a TR of 4 sec. (repetition time) with an in-plane resolution of 3.75 mm×3.75 mm. The echo time was 40 msec and the flip angle was 90°. Whole brain coverage was acquired in 43 slices (slice thickness 3 mm, interslice gap 0.3 mm). Fifty-four T2* -weighted whole brain volumes were acquired in each of the two conditions in both experiments.
Data was analyzed with the XBAM software developed at the Institute of Psychiatry
Self-reported data for within and between-subject differences were calculated using repeated measures analysis of variance (ANOVAs), and post-hoc t-tests to confirm the direction of the differences. Examination of associations between continuous variables was calculated using the Spearman's rank non-parametric correlation coefficient (Spearman's Rho). Associations were deemed significant if correlations met the p-value threshold after Bonferroni correction.
Data from 8 women with BN, 18 women with AN (including 11 women with RAN and 7 women with BPAN) and 24 healthy control women were analysed. Due to time and financial constraints of the study we were unable to increase the subgroup numbers to 12 to meet the minimum p = 0.05 threshold for eighty percent power per voxel
Women with AN and BN had comparable anxiety and depression scores, but those with BN had significantly higher (p<0.001) scores than HC. Women with AN and BN were similarly anxious during the scan when thinking about eating the food: women with BN were significantly more (p<0.001) anxious than the HC. Those women with BPAN had significantly higher anxiety ratings (p<0.001) in response to non-food images than all other groups
In the BN group, duration of illness positively correlated with BMI (Rho = 0.829, p = 0.04) and with levels of self-reported hunger before the scan (Rho = 0.478, p = 0.04).
These data are shown in
Brain Regions | BA | Laterality | x | y | z | Cluster size (voxels) | Cluster-p |
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Cerebellum | --- | L | −18 | −74 | −23 | 443 | 0.0002 |
DLPFC | 9 | R | 47 | 7 | 30 | 74 | 0.001 |
Precuneus | 39 | R | 40 | −63 | 33 | 119 | 0.002 |
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Cerebellum | -- | L | −25 | −67 | −23 | 41 | 0.001 |
Visual Cortex | 18 | L | −14 | −85 | −13 | 50 | 0.001 |
DLPFC | 9 | R | 40 | 4 | 26 | 66 | 0.002 |
Precuneus | 7 | --- | 0 | 41 | 46 | 179 | 0.0006 |
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Cerebellum | --- | L | −4 | −56 | −36 | 111 | 0.0008 |
Cerebellum | --- | R | 25 | −63 | −20 | 389 | 0.0002 |
SMA | 6 | R | 22 | −4 | 53 | 124 | 0.0009 |
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Visual Cortex | 18 | R | 11 | −81 | −4 | 1416 | 0.01 |
DLPFC | 9 | L | −33 | −30 | 28 | 154 | 0.01 |
Insular Cortex | 13 | R | −46 | 10 | −4 | 168 | 0.01 |
Precentral Gyrus | 3 | L | −54 | −15 | 28 | 2774 | 0.01 |
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Cerebellum | --- | L | −4 | −63 | −20 | 497 | 0.0002 |
STG | 22 | R | 51 | −11 | −7 | 300 | 0.0002 |
MTG | 22 | R | 51 | −37 | 7 | 78 | 0.002 |
Caudate | --- | L | −4 | 0 | 20 | 236 | 0.0003 |
Data are shown in
T-value bar illustrates t-value scores represented by cluster on the brain map.
Brain Regions | BA | Laterality | x | y | z | Cluster size (voxels) | Cluster-p |
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Parietal lobe | 2 | R | 54 | −26 | −35 | 43 | 0.003 |
PCC | 31 | L | −11 | −52 | 46 | 13 | 0.006 |
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Precentral Gyrus | 6 | R | 43 | −4 | 43 | 20 | 0.008 |
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ITG | 37 | L | −36 | −56 | −17 | 33 | 0.008 |
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Caudate | --- | R | 40 | −4 | 13 | 48 | 0.004 |
STG/Insula | 22 | R | 14 | 7 | 21 | 68 | 0.005 |
SMA | 6 | L | −43 | 4 | 43 | 57 | 0.003 |
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ITG | 21 | L | −58 | −4 | −10 | 7 | 0.008 |
Fusiform Gyrus | 18 | L | −4 | −67 | −10 | 35 | 0.005 |
PCC | 23 | --- | 0 | −41 | 13 | 43 | 0.005 |
ITG | 21 | R | 47 | −37 | 36 | 62 | 0.001 |
IPL | 7 | L | −4 | −52 | 46 | 41 | 0.001 |
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Cerebellum | --- | L | −18 | −63 | −40 | 29 | 0.004 |
PHG | 28 | L | −22 | 4 | −26 | 12 | 0.004 |
PCC | 31 | L | −4 | −67 | 26 | 23 | 0.008 |
SMA | 6 | R | 25 | 7 | 53 | 32 | 0.008 |
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STG/Insula | 38/13 | L | 54 | −26 | −7 | 18 | 0.001 |
STG/Insula | 22/13 | R | −51 | −15 | 0 | 17 | 0.001 |
Visual Cortex | 31 | L | 44 | −67 | 26 | 12 | 0.002 |
Compared to the AN group, the BN group had relatively reduced activation to food images in the right parietal lobe (x = 54, y = −26, z = 35 [BA 2], and left dorsal posterior cingulate cortex (x = −11, y = −52, z = 46 [BA 31]), and increased activation in the right caudate (x = 40, y = −4, z = 13), right superior temporal gyrus (x = 14, y = 7, z = 21 [BA 22]) and left supplementary motor area (x = −43, y = 4, z = 43 [BA 6]).
Compared to the RAN group, the BN group showed relatively increased activation in the bilateral inferior temporal lobe (x = −58, −4, −10; x = 47, y = −37, z = 36 [BA 21]), left visual cortex (x = −4, −67, −10 [BA 18], posterior cingulate (x = 0, y = −41, z = 13 [BA 23]), and the left inferior parietal lobe (x = −4, y = −52, z = 46 [BA 7]). The BN group compared to the RAN group showed relative deactivation to food images in the right precentral gyrus (x = 43, y = −4, z = 43 [BA 6]).
Compared to the BPAN group, the BN group had relatively greater activation in the left cerebellum (x = −18, y = −63, z = −40), left parahippocampal gyrus (x = −22, y = 4, z = −26 [BA 28]), left posterior cingulate cortex (x = −4, y = −67, z = 26 [BA 31]), right supplementary motor area (x = 25, y = 7, z = 53 [BA 6]). The BN group had deactivation relative to the BPAN group in the left inferior temporal gyrus (x = −36, y = −56, z = −17 [BA 37]).
In the AN group, 10/18 women were on SSRI medication. As this might alter neural activation
We found no significant correlations between any significant clusters of neural activation and participant demographics.
Using a novel fMRI paradigm, whereby participants thought about eating food shown in images rather than passively viewing them, we have compared neural responses in women with BN and AN. These exploratory data provide the first evidence that patterns of food consumption (e.g. binges) combined with degree of restraint over eating behaviour may alter how the brain responds when thinking about eating food. However, caution must be exercised; despite stringent threshold corrections, the small sample sizes make these intriguing results somewhat tentative at this stage, and in need of further clarification with larger cohorts. Activation of the dorsolateral prefrontal cortex, visual cortex and cerebellum in response to food versus non-food images was found in women with AN and BN. Additionally, women with BN show greater somatosensory and motor responses in the right insular cortex and post-central gyrus. Women with BN showed increased activation in somatosensory, motor and appetitive regions in comparison to AN and HC. Furthermore, women with BPAN had reduced activation in comparison to women with BN in regions associated with appetitive and motor responses. Thus, although women with BPAN partake in binge eating and purging behaviour in a similar way to women with BN, their heightened control over eating (as shown by an emaciated body at less than 85 percent of normal body weight) may be achieved by a reduced drive to eat over the long term. Thus, these results suggest a clear BN-specific map of brain activation in response to thinking about eating food shown in images, which is primarily characterized by signs of increased appetitive, somatosensory and motor responses, in parallel with activation of prefrontal cortex cognitive inhibition. However, these intriguing suggestions need to be tested further.
Activation of regions associated with motor responses in women with BN, such as the caudate, supplementary motor area and the precentral gyrus suggests an increased appetitive response to food images. This pattern of activation accords with other fMRI studies of people who binge-eat
We also observed an increased right dorsolateral prefrontal cortex (DLPFC) response to the food versus non-food images, but this was comparable in both eating disordered groups (there was no significant differential DLPFC activation when women with AN and BN were compared). The DLPFC forms part of the cognitive control network, and is associated with restriction of appetitive responses
The balance between these behaviours is likely dependent on the level of bottom-up impingement on cognitive control, as has been shown in two studies with conflicting results: one shows greater, while the other reduced DLPFC activation (Lock et al., 2011; Marsh et al., 2009, respectively). Both studies examined response inhibition in females with BN, one study using the ‘Go/No-Go’ task
The insular cortex functions as an intermediary between the PFC and striatum activation, with dense functional connectivity between these regions, creating an emergent sentience of bodily state
Both BN and AN groups demonstrated an increased visual cortex response during the food versus non-food contrast. However, women with BN had a reduced visual cortex response in comparison to HC. Visual cortex activation usually reflects attention towards the stimuli. Studies of attentional bias using the Stroop task show that women with BN have a greater attentional bias to food stimuli than HC
Additionally, the women with BN had significantly higher restraint scores (EDE-Q) than those with AN, and the women with BPAN had the highest restraint score, which is in line with observations that people who binge are often relapsing from attempts at restraint
It would be of benefit in future fMRI studies to compare the neural responses to high versus low calorie food images, as it has not been done in bulimic women. In healthy women it has been shown that images of high calorie foods activate brain regions associated with somatosensory responses and reward more so than compared to low calorie food images
Additionally, future studies should ensure a totally homogeneous sample of AN women and a much larger sample size, unlike in this preliminary study, where we include 11 restricters and 7 binge-purgers in our total AN group. It could be argued that the binge-purge AN subtype bear similarities with the BN group, by the very nature that both groups partake in binge eating behaviour. However, a counter-argument is that, based on the observation that they were severely underweight, all the women with AN in this study (regardless of subtype) were more successful at restricting their food intake over the long-term than the women with BN. This was also reflected in reduced activation of appetitive and motor brain regions to food images in the women with BPAN compared to BN, and that differences on behavioural measures were comparable between BN v BPAN and between BN v RAN.However, one solution would have been to remove the binge-purgers from our total AN group. However, by including the broad range of AN pathologies we can pinpoint in this cohort the one factor they have in common: restrained eating behaviour that results in self-starvation and a dramatic loss of weight. Thus, we have compared an inhomogeneous group of AN women (who all restrict their food intake) with a group of BN women, to localise differential neural activation associated with long-term restriction of food intake.
There are some limitations to this study: the sample size in the BN group is small (n = 8), and so caution must be exercised when generalising to the BN phenotype. However, in an attempt to overcome the small group numbers, we took the relatively uncommon step of using stringent False Discovery Rate (FDR) correction at both the voxel and cluster level to ensure a rate of a maximum of one false positive. In addition, we provide effect sizes for all demographic data. Furthermore, we did not examine differential neural responses to high versus low calorie food images: by doing this we could examine activation to stimuli of different motivation value. Moreover, unlike in this study, future studies should include a homogeneous and larger sample of women with AN, and also men It is entirely plausible that the small percentage of men who suffer from AN and exhibit the same symptoms also show similar patterns of neural activation to food images. Finally, we used the EDE-Q rather than the EDE to gauge eating disorder pathology, which has been shown to be a good measure overall, but weaker for bingeing behaviour
The data from this and other studies allow the following tentative conclusions that are in need of further testing. People with BN have increased appetitive and motor responses to food stimuli in parallel with varying (and perhaps sporadic) levels of cognitive inhibition arising from the DLPFC. An imbalanced convergence on the insular cortex between these cortical and subcortical processes alters interoceptive awareness and contributes to binge eating, purging and disrupted self-regulation. Future fMRI studies of BN should seek to confirm these findings and to extend knowledge of the interactions between the DLPFC, insular cortex and caudate, perhaps by using dynamic causal modelling (DCM).
Demographic characteristics and self-report measures: demonstrating the mean values, standard deviations, and differences in scores between anorexic and bulimic women.
(DOCX)
With thanks to Dr. Christian Benedict, from the Department of Neuroscience, Uppsala University, Sweden, for his helpful comments on this manuscript.