Brain Responses during Anticipation and Consumption of Palatable Food in Women with and without Bulimia Nervosa or Binge Eating Disorder: disorder-related changes and modulation by intranasal oxytocin

Brain Responses during Anticipation and Consumption of Palatable Food in Women with and without Bulimia Nervosa or Binge Eating Disorder: disorder-related changes and modulation by intranasal oxytocin | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Brain Responses during Anticipation and Consumption of Palatable Food in Women with and without Bulimia Nervosa or Binge Eating Disorder: disorder-related changes and modulation by intranasal oxytocin Daniel Martins, Monica Leslie, Ottavia Dipasquale, Jenni Leppanen, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6207163/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 14 You are reading this latest preprint version Abstract Background: Bulimia nervosa (BN) and binge eating disorder (BED) are marked by recurrent episodes of binge-eating despite negative consequences. Although dysregulated reward processing has been proposed as a key mechanism, experimental evidence has been inconsistent. Intranasal oxytocin (OT), a neuropeptide involved in reward modulation and appetite regulation has been suggested as a potential treatment; however, its neurobiological effects remain unclear. This study examined brain responses during palatable food anticipation and consumption in BN/BED patients versus healthy controls and evaluated OT’s modulatory impact. Methods: In a randomized, double-blind, placebo-controlled, crossover fMRI study, 24 women with BN/BED and 23 healthy controls received 40 IU of intranasal OT or placebo prior to scanning. During fMRI, participants experienced both anticipation and receipt of palatable (chocolate milk) and neutral (water) stimuli while providing subjective ratings of pleasantness, intensity, and anxiety. Effects of diagnosis, treatment, and their interaction were analyzed using both frequentist and Bayesian methods. Results: Compared with controls, BN/BED participants rated both stimuli as less pleasant and more anxiety-provoking. fMRI revealed significantly greater insula activation during palatable food receipt in BN/BED. In contrast, nucleus accumbens activity did not differ between groups. OT suppressed hypothalamic responses to palatable taste across groups, without significantly affecting behavioral ratings or other regions. Conclusion: These findings challenge the view that binge eating is solely driven by reward dysfunction and highlight a potential role for altered sensory/interoceptive processing in BN/BED. Although OT modulated hypothalamic activity, its broader clinical utility remains uncertain, warranting further dose-response studies to determine clinical efficacy. Health sciences/Diseases/Psychiatric disorders Biological sciences/Drug discovery Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Bulimia nervosa (BN) and binge eating disorder (BED) are eating disorders characterized by recurrent loss-of-control binge eating 1 . These disorders are associated with significant physical and psychological comorbidities, contributing to a profound burden on individuals and healthcare systems. Despite advances in treatment, remission rates remain modest 2 , 3 , highlighting the urgent need for more effective and targeted interventions. To this end, understanding the neurobiological mechanisms that underpin binge eating behavior is crucial for identifying novel therapeutic targets. The Addictive Appetite Model provides a biologically informed theoretical framework for understanding of BN and BED 4 , 5 . This framework draws parallels with substance use disorders to posit that dysregulated reward processing plays a central role in perpetuating binge eating behaviors. Specifically, it suggests that individuals with BN and BED experience heightened neural sensitivity to the anticipation of food, particularly within the midbrain and ventral striatum. This heightened anticipatory response drives strong motivational states and cravings for palatable, high-calorie foods, reinforcing the binge episodes. However, upon consuming these foods, a blunted neural response to the actual receipt of food in regions like the nucleus accumbens (NAcc) undermines the expected hedonic satisfaction, creating a mismatch between the anticipated and experienced rewards. This reward-processing imbalance may create a cycle of maladaptive behavior where the heightened anticipation promotes overeating, while the diminished reward receipt fails to satiate or regulate the behavior, reinforcing further binge episodes as individuals attempt to achieve the desired gratification. Over time, this dysregulation may further alter reward circuitry, akin to neuroadaptations seen in substance use disorders, where excessive engagement with the addictive stimuli leads to increased anticipatory salience and diminished hedonic impact. The repetitive engagement with binge eating behavior could thus perpetuate itself, as the neural imbalance strengthens and becomes more ingrained 4 . While preclinical models of binge eating 6 , 7 and neuroimaging studies on substance abuse 8 /food addiction 9 support the Addictive Appetite Model, human neuroimaging findings in BN and BED populations remain inconsistent. For instance, Bohon and Stice reported no significant differences in basal ganglia or orbitofrontal cortex (OFC) activation during food reward processing in women with BN compared to healthy controls (HC) 10 . Conversely, Simon et al. observed heightened medial OFC responses to food receipt in individuals with BN and BED, a region implicated in encoding reward value 11 . While it is likely that these discrepancies might reflect methodological differences in task design (Simon et al. lacks the granularity provided by separate anticipation and receipt phases) and sample characteristics, more targeted investigations to clarify how reward circuits are altered in BN and BED during anticipation and receipt of food rewards are paramount to further test the the Addictive Appetite model. Intranasal oxytocin has emerged as a promising candidate for intervention in BN/BED. Oxytocin receptors are widely expressed in key regions implicated in reward and appetite regulation, including the NAcc, ventral tegmental area (VTA), and hypothalamus 12 . Oxytocin also exerts well-documented functional effects on reward processing, with relevance for appetite regulation 13 – 18 . For instance, oxytocin administration into the NAcc core suppresses both hunger-driven and palatable food intake in non-deprived animals 19 , while also reducing methamphetamine-seeking behavior in rats 20 , highlighting its broader influence on compulsive reward-driven behaviors. Clinically, intranasal oxytocin has demonstrated potential in reducing hedonic overeating 21 – 23 , including in BN 24 . However, current evidence is inconsistent. For instance, our recent work found no significant effects of a divided 64IU dose on caloric consumption in BN/BED 25 . This highlights the need for further investigation into mechanisms of action as it is plausible that subtle effects of intranasal oxytocin on appetitive brain circuits may not reach full behavioral expression at the doses and time points measured in existing studies. The current study had two complementary aims: (1) to test the Addictive Appetite Mode l predictions in women with BN and BED, focusing on reward processing during the anticipation and receipt of palatable food; and (2) to evaluate the effects of intranasal oxytocin, exploring its therapeutic potential. Specifically, we hypothesized that women with BN and BED would show heightened blood oxygenation dependent (BOLD) functional magnetic resonance imaging (fMRI) response in the NAcc during palatable food anticipation but reduced response during palatable food receipt compared to controls. We further hypothesized that oxytocin would mitigate these differences. Exploratory whole-brain analyses were conducted to identify additional regions influenced by oxytocin or eating disorder status. Methods Participants We recruited a total of 52 women through advertisements: 20 women met DSM-5 criteria for BN, 5 women met DSM-5 criteria for BED, and 27 women had no current or prior history of an eating disorder. Details regarding participants’ demographic and clinical characteristics are presented in Table 1 . Further details regarding the eligibility criteria and clinical profile of participants are presented in the Supplementary Material. Sample size was decided based on a priori power analysis implemented in G*Power 26 . This analysis estimated that a total sample size of 50 participants would be needed to detect a medium effect size (partial eta square of 0.04) in a 2-way within-between interaction with 80% power. Ethical approval for the study was granted by the London – Camberwell St Giles Research Ethics Committee (Reference: 14/LO/2115). Study Design This proof-of-concept study employed a double-blind, placebo-controlled, crossover design. Each participant was invited to come to the laboratory on three occasions. The first occasion was a preliminary screening visit in which each participant signed informed consent and was screened for eligibility for the study. Each participant was then given a link to an online survey in which they could provide basic demographic data (including age and education level) before the first experimental visit. Next, participants attended two counterbalanced sessions (oxytocin/placebo) held two days apart to ensure drug washout and that each participant completed each of the experimental study sessions whilst in the same phase of the menstrual cycle. After fasting for 2.5 hours, they self-administered 40 IU oxytocin/placebo using a standard nasal spray. All sessions were conducted in the afternoon to avoid potential circadian confounds. The dose selection and route of administration were informed by previous evidence showing suppression of caloric intake in one study with BN patients 24 , and modulation of brain perfusion at rest in healthy men in another two studies 27, 28 . The full dose was administered over a series of 10 sprays, each administered 30 seconds apart, alternating nostrils each time following gold-standard recommendations 29 . The fMRI task subsequently commenced 23.16 (±4.46) minutes after the end of drug administration, on average. fMRI Scan Set-Up Each participant lay on the scanning bed with an MRI-compatible flavor-dispensing box (containing cold Evian water and Galaxy chocolate milk) positioned under their knees. A hose delivered the liquids through a disposable mouthpiece, secured with a plastic clamp on the head coil. Participants held a button box for responses. fMRI Task Before each fMRI run, participants rated the pleasantness, intensity, and anxiety of 0.5 mL of chocolate milk and water using a visual analogue scale (VAS) , responding via button presses. During the fMRI task ( Figure 1 ), participants viewed images of a glass of chocolate milk or water for three seconds and indicated the image type using button presses. A fixation cross then appeared for a jittered interval of one to seven seconds. In valid trials, a 0.5 mL squirt of the corresponding liquid was delivered through the mouthpiece, which participants held in their mouth for three seconds before being instructed to swallow following a jittered fixation cross lasting one to nine seconds. In invalid trials, no liquid was delivered, and the fixation cross remained on screen for an additional five seconds before the next trial began. Each run consisted of 50 trials (30 valid and 20 invalid trials) , with 25 images of each stimulus, presented in a pseudo-randomized order. After the first valid trial, participants rated the pleasantness and intensity of the received liquid, repeating this every 10 valid trials. A second fMRI run followed the same procedure, with a newly randomized stimulus order. fMRI Scanning Protocol The images were acquired using a 3.0 Tesla GE unit. Each fMRI run lasted 14 minutes (422 volumes). Four dummy scans were acquired and discarded. Functional images were acquired with 41 slices (3mm thickness, 0.3mm gap, FOV = 240mm, 64×64 matrix, voxel size = 3.75×3.75×3mm). The scan parameters were TE = 30ms, TR = 2000ms, and a 75° flip angle. A 3D high-spatial-resolution, magnetization prepared rapid acquisition T1-weighted scan (FOV of 270mm, TR/TE/TI = 7.31/3.02/400ms) was also acquired at the end of the session. MRI data preprocessing and first-level modelling Preprocessing: We carried out the preprocessing using FEAT, as part of the FMRIB Software Library (FSL) v6.0. Best practice recommendations in taste-related neuroimaging 30 were followed which included: i) standard head motion correction by volume-realignment to the middle volume using MCFLIRT; ii) slice-time correction; iii) skull-stripping of both functional and structural images using the Brain Extraction Tool (BET); iv) denoising using Independent Component Analysis based Automated Removal of Motion Artifacts (ICA-AROMA); v) high-pass filter (0.01 Hz); vii) registration to high-resolution MPRAGE scans via a 6-parameter linear registration (FLIRT) and spatial normalization to the Montreal Neurological Institute (MNI) 152— T 1 2-mm template via a 12-parameter nonlinear registration (FNIRT). Functional images were resampled into the standard space with 2-mm isotropic voxels and were smoothed with a Gaussian kernel of 6-mm full-width at half-maximum. All scans had mean frame-wise displacement < 0.25 mm and were therefore included for further analysis. First-level modelling: We constructed a design matrix with separate regressors (duration = 0) for chocolate or water anticipation (for valid and invalid trials), chocolate or water receipt, the “Swallow” instruction, and VAS completion. Event timings were convolved with a canonical hemodynamic response function. We also included 24 head motion parameters (6 head motion parameters, 6 head motion parameters one time point before, and the 12 corresponding squared items) to model the residual effects of head motion as covariates of no interest – this approach has been shown to more efficiently remove head motion effects from BOLD-fMRI data 31, 32 . We applied pre-whitening to remove residual temporal autocorrelation. The following contrasts at the single-subject level were generated using FSL’s FLAME in mixed-effects mode: (1) chocolate versus water anticipation for both valid and invalid trials; and (2) chocolate versus water delivery. We excluded trials in which participants did not correctly indicate the presence of the chocolate milk image versus water image to ensure that we only included trials where participants paid attention. Statistical analyses Behavioural ratings: First, we averaged ratings for each of the three VAS (hedonic, intensity and anxiety) for each participant, session and stimulus type. Then, we investigated the effects of stimulus, group, treatment, and all possible two- and three-way interactions using two-way mixed ANOVAs and respective Bayesian counterparts as implemented in JASP 0.8.5.1 33-38 . fMRI Regions-of-interest analyses: For the contrast chocolate anticipation vs water anticipation ,our ROI analyses were focused on our primary region, the nucleus accumbens, and five other regions: the midbrain, the putamen, the caudate nucleus, the pallidum and the amygdala (all bilateral). All these regions have been previously shown to be engaged during the anticipation of appetitive stimuli, including palatable food. For the contrast chocolate delivery vs water delivery, we focused on the above six regions plus the insula and the hypothalamus. The insula is part of the primary gustatory cortex and increases in the BOLD signal in the insula have been consistently reported in response to gustatory stimulation 10, 39 . The hypothalamus plays a pivotal role in food intake networks and increases in the BOLD signal in this region have been reported in response to glucose and palatable food (though inconsistently) 40-42 . We used anatomically defined masks to extract the median parameter estimate of all voxels within each ROI from the unsmoothed first-level contrasts using fslmeants . The masks were derived from a high-resolution probabilistic atlas of subcortical structures 43 by thresholding each map to include voxels with 50% probability or higher of belonging to a certain ROI and then binarizing the thresholded maps. The midbrain mask included both VTA and substantia nigra (SN). Since a large proportion of our participants had high levels of drop out of the BOLD signal in the nucleus accumbens 44 , we only extracted data from the voxels of this ROI that had less than 10% of BOLD signal loss in all scans. This allowed us to sample the same number of voxels in each participants/condition while discarding voxels where the BOLD signal could not be measured reliably. The final number of voxels in the nucleus accumbens ROI was 23. We investigated the effects of group, treatment, and group x treatment using two-way mixed ANOVAs. We also conducted exploratory analyses testing for Pearson correlations between parameter estimates reflecting changes in BOLD signal related to the delivery of chocolate and water and: i) hedonic, intensity and anxiety ratings during the task; ii) BMI, eating and affective symptom severity. As a measure of eating symptom severity, we used the global EDEQ scores. Since patients with BN/BED score highly on scales measuring anxiety, stress and depression, and scores on these scales were highly correlated with each other, we used within-group principal component analysis (PCA) on these three measures to obtain a single score reflecting affective/stress symptom severity. The first principal component accounted for 70.81% and 83.47% of the total variance in the patients and HCs, respectively. Correlations were calculated separately for BN/BED and HC participants. In all our analyses, we set statistical significance at p<0.05 (two-tailed), applying false-discovery rate (FDR) correction for the number of ROIs tested. Our Bayesian analyses used the uninformative priors specified as default in JASP. An increase in Bayes Factor (BF) in our analyses corresponds to an increase in evidence in favour of the alternative hypothesis. To interpret BF, we used the Lee and Wagenmakers’ classification scheme 45 : BF < 1/10, strong evidence for the null hypothesis; 1/10<BF<1/3, moderate evidence for null hypothesis; 1/3 < BF 1, anecdotal evidence for the alternative hypothesis; 3<BF 10, strong evidence for the alternative hypothesis. Whole-brain analyses: We also conducted exploratory analyses at the whole-brain level. Using data from the placebo session of our HC group, we investigated main effects of tasks using one-sample T-tests. For the effects of group, treatment, and group x treatment, we took a partitioned errors approach to account for the likely violation of sphericity present in data from full within-subjects designs 46 . Briefly, to calculate the main effect of group, we averaged the first-level maps across treatment levels for each participant and then entered these average maps into an independent samples t -test. To calculate the main effect of treatment, we subtracted the first-level placebo maps from oxytocin maps and then entered these difference maps into a one-sample t -test pooling together HC and BN/BED patients. To calculate the group x treatment interaction, we entered the difference maps described above into an independent samples t -test. For all whole-brain analyses, we applied cluster-based inference within Randomise 41 (5000 permutations), considering a cluster significant if P FWE < 0.05, corrected for multiple comparisons using the null distribution of the maximum cluster size across the image. All statistical analyses (behavioural and fMRI data) were conducted with the researcher unblinded regarding treatment or group status. Results Effects of diagnosis, treatment and diagnosis x treatment on behavioural ratings of taste stimuli We found significant main effects of stimuli for all the three behavioural ratings (Table 2). Post hoc investigations of these effects revealed that chocolate milk was ranked as more palatable (T(47)=5.64, p Tukey < 0.001, d = 1.084), more intense (T(46)=5.83, p Tukey < 0.001, d = 1.408) and more anxiety-provoking (T(50)=2.50, p Tukey = 0.016, d = 0.346,) than water, across groups. We also found significant main effects of group for the hedonic and anxiety ratings. Women with BN/BED also rated both chocolate milk and water as less pleasant (T(47)=3.22, p Tukey =0.018, d= -0.349) and more anxiety-provoking (T(50)=3.74, p Tukey <0.001, d=0.519) than healthy women (Figure 2 and Table 2). None of the remaining effects reached significance; Bayesian analyses were consistent with frequentist analyses (Table 2). Repeating the same analyses but this time including age, BED diagnosis, BMI, phase of menstrual cycle, current medication or comorbidities as covariates of non-interest did not change the overall pattern of results (Supplementary Table S1). Mapping the BOLD responses during the anticipation and delivery of palatable stimuli in the healthy group In the placebo session, during the anticipation phase, observing the cue for chocolate milk as compared to the cue for water (chocolate anticipation vs water anticipation ) was associated with i) increases in the BOLD signal in one cluster spanning the left precentral / postcentral gyri; ii) decreases in the BOLD signal in two clusters spanning the precentral gyrus and occipital cortex, respectively (Figure 3 and Supplementary Table S2). During the delivery phase, the receipt of chocolate milk as compared to the receipt of water (chocolate delivery vs water delivery ) was associated with increases in the BOLD signal in nine clusters spanning the insula / central opercular cortex, cerebellum, and the precentral / postcentral gyri (all bilaterally) (Figure 3 and Supplementary Table S3). Contrary to expectation, we did not observe any changes in the BOLD signal in the basal ganglia or midbrain for either phase. Diagnosis, treatment and diagnosis x treatment effects on BOLD signal changes during palatable food anticipation and delivery For the contrast chocolate anticipation vs water anticipation , we did not find any significant effect of diagnosis, treatment, or diagnosis x treatment in any of the ROIs we tested (Table 3). For the contrast chocolate delivery vs water delivery , we found a significant main effect of diagnosis for the insula ROI, and a significant main effect of treatment for the hypothalamus ROI. None of the remaining effects reached significance (Table 4). As shown in Figure 4, the main effect of group in the insula was driven by an increased BOLD response to chocolate milk (but not water) in women with BN/BED as compared to HCs. The main effect of treatment in the hypothalamus was driven by a decrease in the BOLD response to chocolate milk (but not to water) for oxytocin, compared to placebo, across all participants (Figure 4). Results from Bayesian analyses were consistent with frequentist analyses of the same data (Table 3). Repeating the same analyses including age, BED diagnosis, BMI, phase of menstrual cycle, current medication, or comorbidities as covariates of non-interest did not change the overall pattern of results for the insula ROI; however, for the hypothalamus ROI, the main effect of treatment was no longer significant after FDR correction (Supplementary Tables S4 and S5). We also performed exploratory whole-brain analyses investigating effects of diagnosis, treatment and diagnosis x treatment beyond our pre-selected ROIs but no cluster survived correction for multiple comparisons. Correlations between BOLD signal changes during delivery of palatable stimuli and behavioural ratings or clinical symptoms To help us interpret the potential functional relevance of the diagnosis-related changes in the insula BOLD response to the delivery of taste stimuli, we then sought to investigate whether contrast parameter estimates could predict: i) the behavioral ratings of pleasantness, intensity or anxiety-provoking of the taste stimuli; ii) clinical symptoms (including eating and general psychopathology) and BMI. We did not find any significant correlations in women with BN/BED or HCs (Supplementary Tables S6 and S7). Bayesian correlations were consistent with their frequentist counterparts. Discussion Contrary to our hypotheses we did not observe any significant group differences in NAcc BOLD signal changes during the anticipation or receipt of palatable stimuli. Furthermore, we did not observe any modulatory effect of intranasal oxytocin in this region. In contrast, we observed heightened insula activation in BN/BED participants during the receipt of the palatable stimulus (chocolate milk), consistent with altered sensory and interoceptive processing of palatable stimuli. Oxytocin suppressed hypothalamic responses to palatable stimuli across both groups but did not significantly influence behavioural ratings or insula activity. Altogether, our main findings highlight that binge eating behaviours may involve neural pathways beyond traditional reward circuitry and suggest a potential homeostatic mechanism by which OT may influence appetite regulation, strengthening the rationale for future larger dose-response studies examining its therapeutic potential and optimal dose in BN/BED. The absence of significant group differences in the NAcc during food anticipation or delivery challenges key predictions of the Addictive Appetite Model. This model proposes that BN/BED is characterized by heightened reward anticipation and blunted reward receipt, yet our results indicate minimal involvement of these pathways. Importantly, this lack of group differences cannot be attributed to a failure of BN/BED participants to perceive the stimuli as rewarding. Both groups rated chocolate milk as pleasant, indicating that the stimuli were salient and hedonic. However, the pleasantness ratings did not translate into robust NAcc activation, raising questions about the ability of the task to elicit strong reward responses. Notably, HCs also showed minimal engagement of the NAcc, further suggesting that the experimental paradigm may not have been optimized to activate reward circuits in either group. Factors such as the controlled laboratory setting, the modest volume of chocolate milk delivered (though similar to other studies 47 ), the fat content of the stimuli (as participants might consider foods higher in fat as more rewarding), the satiety state, and the repetitive nature of the task may have attenuated the motivational and hedonic responses to our palatable stimuli 30 . However, we also note the substantial dropout of BOLD signal in the NAcc 44 , 48 , which might have limited statistical power to detect any group or treatment effects if they existed, as we could only sample a small percentage of voxels within this region. While not uncommon in standard acquisitions as ours, this is a methodological aspect future studies should consider, for instance, by attempting to minimise dropout by adjusting the angle of acquisition to maximise coverage of the NAcc and orbitofrontal cortex 44 . We note though that our null findings for the NAcc largely align with previous studies of women with current BN or a history of BN, which also failed to observe differences in BOLD activation in the ventral striatum in response to receipt of expected sweet taste, as compared to control participants 10 , 39 , 49 . One study serves as an exception that instead found heightened BOLD response in the left anterior ventral striatum amongst women with BN, as compared to HC, in response to unsweetened cream versus water 50 . It may, therefore, be the case that disorder-related differences in the degree to which the ventral striatum is recruited during taste stimulation are specific to unsweetened high-fat stimuli, rather than sweet palatable tastes. Nevertheless, on balance, the evidence to date does not support differences in ventral striatum BOLD activation in response to sweet tastes in women with BN versus HC. At the behavioural level, women with BN/BED rated both chocolate and water tastes to be less pleasant, but more anxiety provoking compared to HC ratings, which one might reasonably expect be associated with detectable differences in BOLD response 51 . The decreased pleasantness ratings for the chocolate milk align well with our predictions but the decrease for the water stimuli was unexpected but not implausible if interpreted in the wider context of the emotional relationship BN/BED patients establish with food. Indeed, BN/BED is often accompanied by heightened negative emotionalityparticularly in situations involving food or related stimuli 52 . This pervasive negative emotional context could influence the evaluation of both palatable and neutral stimuli, reflecting a general difficulty in experiencing neutral or positive responses to sensory food stimuli 52 . In contrast to the null findings observed for the ventral striatum, we did observe a greater chocolate-versus-water BOLD contrast in the insula amongst women with BN/BED versus healthy comparison women. These findings concur with previous neuroimaging studies in BN, which have repeatedly reported differences in activation of the insula in response to gustatory stimulation 10 , 39 . The mid-insula acts as the primary taste cortex, and the anterior insula plays an important role in the integration gustatory stimuli with information about the texture and temperature of food stimuli 53 . Thus, this finding is compatible with an interpretation of group differences in primary processing of food stimuli, although this is by no means the only explanation for our observations. Neural activity of the insula is also associated with a wide range of other cognitive and emotional processes, including craving 54 and disgust 55 . Therefore, in the absence of significant correlations between insula responses and any of our behavioural ratings or symptoms, it is likely that differences in the insula responses reflect mostly implicit processes that do not reach conscious perceptions. One such process might be interoception, as the insula is also a key hub for interoceptive processing 56 , which involves the perception and interpretation of internal bodily states such as hunger, fullness, and the sensory experience of eating 57 . Within the Predictive Coding Model, the insula plays a critical role in computing interoceptive prediction errors—comparing expected bodily sensations (e.g., the anticipated fullness from food) with actual sensory input 58 . In BN/BED, prediction errors may be miscalibrated, leading to exaggerated sensory-emotional responses to food consumption. For individuals with BN/BED, this hyperactivation may make the sensory experience of eating palatable foods more salient, potentially contributing to loss of control over eating. Such findings align with previous work indicating that individuals with BN/BED exhibit impaired interoceptive awareness and greater reliance on external cues rather than internal satiety signals to regulate eating behavior 59 . In contrast with our predictions, intranasal oxytocin did not modulate BOLD responses to palatable taste anticipation and delivery in the ventral striatum. Previous evidence from animal studies has supported an anorexigenic neural pathway from oxytocinergic neurons in the paraventricular nucleus of the hypothalamus, which suppress the activity of dopaminergic neurons in the ventral tegmental area, ultimately inhibiting the activity of neurons in the NAcc which underpin reward-related feeding 59 . However, the lack of oxytonergic effects in the current study may be due to insufficient engagement of the NAcc during the task, limiting the ability to detect modulation by oxytocin. Instead, the only drug difference observed was in the hypothalamus. Visual inspection of the data revealed that this difference was largely driven by oxytocin-induced suppression of BOLD response to chocolate taste, which did not occur in response to water. This finding partially corresponds with van der Klaauw et al. 60 , who reported that oxytocin suppresses BOLD response within the hypothalamus in response to visual food stimuli in a mixed sample of men and women. However, the lack of oxytocin effects on behavioural ratings suggests that these neural changes may not immediately translate into observable shifts in appetite or eating behaviour, at least under controlled experimental conditions. It is possible though that this finding may have functional significance for eating behaviour. For example, previous work has highlighted that the anorectic effects of the anti-obesity drug sibutramine are likely mediated by suppression of hypothalamic response to visual food stimuli 61 . This underscores the need to explore alternative dosing regimens or contexts where oxytocin’s effects may be more pronounced. This study has several strengths that enhance the reliability and generalizability of the findings. First, the robust double-blind, crossover design minimizes biases and individual variability, providing a high degree of control over potential confounding factors. Second, the inclusion of participants with comorbidities 62 and those on psychoactive medications 63 , 64 reflects the real-world clinical population of individuals with BN and BED, increasing the ecological validity of the results. Third, we applied a data-driven approach to denoise the BOLD signal, which boosts signal-to-noise ratio. We also complemented the standard frequentist analyses with Bayesian analyses, which allowed a more insightful interpretation of our null findings as reflective of lack of group and treatment effects given the data. However, our study was not without limitations. First, the conditional effect of oxytocin on BOLD response in the NAcc might have been greater at an alternative time frame or dose of administration. Indeed, we chose the current dose of 40IU based on previous evidence from our own lab indicating that this dose effectively reduces neural activation in regions of interest, particularly within the basal ganglia in healthy men 27 , 28 . However, the latest evidence from the current participant sample failed to replicate effects of oxytocin on cerebral blood flow in women at the same dose and time frame of administration 65 , and two other studies from our research team suggest that lower doses might in fact be more effective in modulation brain responses in the amygdala at rest 66 and midbrain – subgenual anterior cingulate circuitry during prosocial learning 67 . It is, therefore, possible that more pronounced changes in BOLD response might be observed to the anticipation and receipt of palatable taste following lower doses of intranasal oxytocin, as compared to the 40IU dose used in the current study. We also included women across different stages of the menstrual cycle (though each woman was tested at the same phase of the cycle for OT and placebo), including some women taking hormonal contraception, due to the practical challenges associated with recruiting an adequate sample of women with BN or BED. While this decision may improve ecological validity due to the recruitment of a more representative sample of British women, previous research has found that hormonal contraception can blunt the effects of oxytocin on reward processing 68 . Overall, our work underscores the importance of expanding theoretical frameworks for BN and BED to include sensory and interoceptive processes alongside reward dysregulation. It also suggests a potential mechanism by which oxytocin may influence appetite regulation, strengthening the rationale for future larger dose-response studies examining its therapeutic potential and optimal dose in BN/BED. Declarations Conflict of interest: Nothing to declare. Acknowledgements: ML was supported by grants from the Swiss Fund for Anorexia Nervosa, the Guy’s and St Thomas’ NHS Foundation Trust, and a King’s Health Partners Challenge Fund. YP was supported by an Economic and Social Research Council fellowship (grant number ES/K009400/1). JT, OD and DM were supported by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. CRediT author statement: DM : data curation (equal), formal analysis (lead), visualisation (lead), writing (original draft) (equal), writing (review and editing) (equal). ML: data curation (equal), formal analysis (supporting), investigation (lead), project administration (lead), writing (original draft) (equal), writing (review and editing) (supporting). OD: formal analysis (supporting). JL: conceptualisation (supporting), writing (review and editing) (supporting). JT: conceptualisation (equal), supervision (equal), funding acquisition (lead), writing (review and editing) (supporting). YP: conceptualisation (equal), supervision (equal), funding acquisition (supporting), writing (review and editing) (equal). References Kahn DA, Reviewed b. DSM-5-TR Clinical Cases. 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Oxytocin modulates neurocomputational mechanisms underlying prosocial reinforcement learning. Prog Neurobiol 2022; 213: 102253. Scheele D, Plota J, Stoffel-Wagner B, Maier W, Hurlemann R. Hormonal contraceptives suppress oxytocin-induced brain reward responses to the partner's face. Soc Cogn Affect Neurosci 2016; 11 (5) : 767-774. Tables Table 1. Descriptive demographic and clinical data. Healthy Control ( n = 27) BN/BED ( n = 25) Median IQR Median IQR Age 23.50 5.50 23.50 9.75 BMI 22.04 1.76 23.09 3.87 RQF Education Level 6 4 4.5 3 Global EDE-Q 0.36 0.78 4.34 1.74 EDE-Q Restraint 0.40 0.70 4.00 2.10 EDE-Q Eating Concern 0.00 0.20 4.20 1.90 EDE-Q Weight Concern 0.40 0.85 4.80 1.50 EDE-Q Shape Concern 0.63 1.44 5.63 1.63 DASS - Depression 0.00 2.50 24.00 15.00 DASS - Anxiety 0.00 2.00 10.00 12.00 DASS - Stress 3.00 6.00 20.00 18.00 Note. BN = bulimia nervosa; BED = binge eating disorder; IQR = interquartile range; BMI = body mass index; RQF = Regulated Qualifications Framework. Table 2. Effects of stimuli, diagnosis, treatment and respective interactions on pleasantness, intensity, and anxiety ratings of taste stimuli. Hedonic Intensity Anxiety Statistics F(1, 206) p BF 01 F(1,207) p BF 01 F(1,207) p BF 01 Diagnosis 5.98 0.018 4.237 0.841 0.364 0.288 14.00 < 0.001 43.295 Treatment 0.029 0.864 0.287 0.256 0.615 0.159 1.027 0.316 0.546 Stimuli 57.572 < 0.001 8.69x10 17 95.201 < 0.001 1.18x10 30 6.234 0.016 2.154 Diagnosis x Treatment 0.117 0.733 0.110 0.572 0.453 0.233 1.929 0.171 0.296 Diagnosis x Stimuli 0.014 0.907 0.152 1.462 0.233 1.002 0.483 0.490 0.210 Stimuli x Treatment 0.038 0.847 0.103 0.008 0.931 0.204 0.401 0.529 0.183 Diagnosis x Treatment x Stimuli 2.127 0.151 0.419 0.628 0.432 0.277 0.243 0.624 0.323 Table 3. Effects of diagnosis, treatment and diagnosis x treatment on BOLD responses during anticipation of palatable as compared to tasteless stimuli. Region Main effect diagnosis Main effect treatment Interaction diagnosis x treatment F(1,103) p p FDR BF 01 F(1,103) p p FDR BF 01 F(1,103) p p FDR BF 01 Nucleus Accumbens 0.009 0.923 0.958 0.174 1.168 0.285 0.767 0.277 0.176 0.677 0.932 0.066 Midbrain 0.268 0.607 0.958 0.183 0.052 0.821 0.821 0.149 0.053 0.822 0.932 0.047 Caudate 0.031 0.861 0.958 0.169 0.215 0.645 0.774 0.167 0.776 0.383 0.932 0.061 Putamen 0.003 0.958 0.958 0.183 0.633 0.430 0.767 0.200 0.007 0.932 0.932 0.049 Pallidum 0.019 0.891 0.958 0.188 0.713 0.402 0.767 0.218 1.329 0.254 0.932 0.105 Amygdala 0.009 0.923 0.958 0.169 0.439 0.511 0.767 0.183 0.065 0.800 0.932 0.045 Table 4. Effects of diagnosis, treatment and diagnosis x treatment on BOLD responses during delivery of palatable as compared to tasteless stimuli. Region Main effect diagnosis Main effect treatment Interaction diagnosis x treatment F(1,103) p p FDR BF 01 F(1,103) p p FDR BF 01 F(1,103) p p FDR BF 01 Nucleus Accumbens 0.068 0.796 0.928 0.178 0.207 0.651 0.856 0.163 0.281 0.599 0.858 0.047 Midbrain 1.240 0.271 0.875 0.269 0.033 0.856 0.856 0.154 0.458 0.502 0.858 0.063 Caudate 0.387 0.537 0.928 0.211 0.100 0.753 0.856 0.156 0.391 0.535 0.858 0.058 Putamen 0.140 0.709 0.928 0.189 0.175 0.678 0.856 0.158 0.059 0.808 0.858 0.042 Pallidum 0.008 0.928 0.928 0.178 0.114 0.737 0.856 0.157 0.100 0.753 0.858 0.046 Insula 20.600 0.001 0.008 318.932 0.054 0.817 0.856 0.176 0.032 0.858 0.858 0.191 Hypothalamus 0.0125 0.911 0.928 0.219 10.474 0.002 0.016 32.294 0.370 0.564 0.858 0.255 Amygdala 0.976 0.328 0.875 0.250 1.151 0.289 0.856 0.269 0.049 0.825 0.858 0.082 Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files OXYFOODTasteSupplementfinal.docx Supplementary Cite Share Download PDF Status: Under Review Version 1 posted Unknown event 10 Apr, 2026 Editorial decision: Reject after peer review 07 Nov, 2025 Reviewer # 5 agreed at journal 04 Nov, 2025 Review # 3 received at journal 26 Oct, 2025 Reviewer # 4 agreed at journal 25 Oct, 2025 Reviewer # 3 agreed at journal 20 Oct, 2025 Review # 2 received at journal 16 Oct, 2025 Reviewer # 2 agreed at journal 06 Oct, 2025 Reviewer # 1 agreed at journal 29 Jul, 2025 Reviewers invited by journal 25 Jul, 2025 Editor assigned by journal 18 Mar, 2025 Submission checks completed at journal 13 Mar, 2025 First submitted to journal 12 Mar, 2025 Unknown event 12 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6207163","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":431214813,"identity":"a2bc79e7-3339-4077-a2e8-80bc58d4163a","order_by":0,"name":"Daniel Martins","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYDCCAyBUAGfbGDCwQzgG+LWApZlB7DQDIE1YCwNMCxAcJqyF7/jZgwc+GDBE888+f/BwwZ/zxvzNDIwffjAcNsalRfJMXsLBGQYMuTPOJTMcntl220ziMAOzZA/DYTNcWgwO5Bgc5gFqaTjDzHCYt+G2jQHQYdJAF9rg1HL+jcHhP0At80FaeP6cA2lh/o1Xyw2gLUCv5m4Aa2E7YAbUwgayBafDJG+8MTjYYyCRu/EMs8Fh3rZkY4nDjG2WPQbpOL3Pdz7H+MOPCpvceWcYH3/m+WNn2N/efPjGjwprwwZceiBAApnD2IAvIkfBKBgFo2AUEAEAfYBVtqaHgLwAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0239-8206","institution":"Institute of Psychiatry, Psychology and Neuroscience, King's College London","correspondingAuthor":true,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Martins","suffix":""},{"id":431214814,"identity":"88e1ded0-3fa6-42f9-bfd3-01bc36f6e667","order_by":1,"name":"Monica Leslie","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Monica","middleName":"","lastName":"Leslie","suffix":""},{"id":431214815,"identity":"02c5c47f-3e18-43e8-82e7-f4f9c180d7ed","order_by":2,"name":"Ottavia Dipasquale","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ottavia","middleName":"","lastName":"Dipasquale","suffix":""},{"id":431214816,"identity":"5ead7ac1-a037-42fb-972c-0aa6af624a0f","order_by":3,"name":"Jenni Leppanen","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jenni","middleName":"","lastName":"Leppanen","suffix":""},{"id":431214817,"identity":"234e4414-772c-4ec8-9b26-d55157fcfd2e","order_by":4,"name":"Janet Treasure","email":"","orcid":"https://orcid.org/0000-0003-0871-4596","institution":"South London \u0026 Maudsley NHS Trust Director Eating Disorder Unit and Professor Psychiatry Guys, Kings \u0026 St Thomas Medical School, London","correspondingAuthor":false,"prefix":"","firstName":"Janet","middleName":"","lastName":"Treasure","suffix":""},{"id":431214818,"identity":"7beba8f5-2688-4761-a562-74cd953b65dc","order_by":5,"name":"Yannis Paloyelis","email":"","orcid":"https://orcid.org/0000-0002-4029-3720","institution":"Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK","correspondingAuthor":false,"prefix":"","firstName":"Yannis","middleName":"","lastName":"Paloyelis","suffix":""}],"badges":[],"createdAt":"2025-03-11 22:40:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6207163/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6207163/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82143894,"identity":"f57dc9d2-a1c5-478f-9692-1d3e069adb80","added_by":"auto","created_at":"2025-05-07 06:43:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":218498,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTaste\u003c/strong\u003e \u003cstrong\u003eparadigm\u003c/strong\u003e. Participants were presented with a series of pictures of either a glass of chocolate milk or water (cue) and were instructed to press the left or right button each time they were presented with a picture of a glass of chocolate milk or water, respectively. For valid trials (A), the presentation of the picture of water or chocolate milk was followed by a squirt of the drink corresponding with the image they had just seen (delivery). Participants were instructed to hold the drink in their mouth for 3 seconds. This delivery period was then followed by another fixation cross. At this point the participant was presented with a visual instruction to “Swallow”. For invalid trials (B), the fixation cross presented after the cue remained on the screen for an additional fixed period of 5 seconds.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-6207163/v1/956616ce4a66ee957652706d.png"},{"id":82147153,"identity":"87e28a43-1a99-479a-8a98-6d02dee57664","added_by":"auto","created_at":"2025-05-07 06:59:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":297224,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWomen with BN/BED rated both palatable and neutral taste stimuli as less pleasant and more anxiety-provoking. \u003c/strong\u003eThe violin and box plots show the distribution of the marginal means of the hedonic and anxiety ratings for each group.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-6207163/v1/64982032a43c48f5baa8002d.png"},{"id":82145162,"identity":"9ecdb474-dde4-480a-b2b3-89affd15ed74","added_by":"auto","created_at":"2025-05-07 06:51:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":491942,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBOLD responses during the anticipation and delivery of palatable stimuli. \u003c/strong\u003eImages are shown as T-statistics. All clusters were significant after correction for multiple comparisons using Randomise (FSL), a non-parametric test (p\u003csub\u003eFWE\u003c/sub\u003e\u0026lt;0.05). L – left; R – right.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-6207163/v1/5c560af9d6a79363aac1b1b5.png"},{"id":82143897,"identity":"432b9fda-2c58-4564-9f4e-853f47bbc44a","added_by":"auto","created_at":"2025-05-07 06:43:35","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":501396,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMain effects of group and treatment on the BOLD response to the delivery of palatable stimuli in the insula (A) and hypothalamus (B) regions-of-interest. \u003c/strong\u003eThe violin and box plots show the distribution of the Z-scores of the median parameter estimates within each anatomical ROI. L – left; R – right.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-6207163/v1/ab4508d3be2038e676da63ad.png"},{"id":95527631,"identity":"e587408d-6cc5-4fb1-a2c2-510685929ee0","added_by":"auto","created_at":"2025-11-10 10:14:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3221767,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6207163/v1/66668369-549b-4826-b1bd-b65715792580.pdf"},{"id":82145161,"identity":"a8789111-d7f4-42fa-a83b-bea57072f37c","added_by":"auto","created_at":"2025-05-07 06:51:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":35998,"visible":true,"origin":"","legend":"Supplementary","description":"","filename":"OXYFOODTasteSupplementfinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-6207163/v1/ce212e6cd9c6d75a820179ee.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Brain Responses during Anticipation and Consumption of Palatable Food in Women with and without Bulimia Nervosa or Binge Eating Disorder: disorder-related changes and modulation by intranasal oxytocin","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBulimia nervosa (BN) and binge eating disorder (BED) are eating disorders characterized by recurrent loss-of-control binge eating\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. These disorders are associated with significant physical and psychological comorbidities, contributing to a profound burden on individuals and healthcare systems. Despite advances in treatment, remission rates remain modest\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, highlighting the urgent need for more effective and targeted interventions. To this end, understanding the neurobiological mechanisms that underpin binge eating behavior is crucial for identifying novel therapeutic targets.\u003c/p\u003e \u003cp\u003eThe Addictive Appetite Model provides a biologically informed theoretical framework for understanding of BN and BED\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. This framework draws parallels with substance use disorders to posit that dysregulated reward processing plays a central role in perpetuating binge eating behaviors. Specifically, it suggests that individuals with BN and BED experience heightened neural sensitivity to the anticipation of food, particularly within the midbrain and ventral striatum. This heightened anticipatory response drives strong motivational states and cravings for palatable, high-calorie foods, reinforcing the binge episodes. However, upon consuming these foods, a blunted neural response to the actual receipt of food in regions like the nucleus accumbens (NAcc) undermines the expected hedonic satisfaction, creating a mismatch between the anticipated and experienced rewards. This reward-processing imbalance may create a cycle of maladaptive behavior where the heightened anticipation promotes overeating, while the diminished reward receipt fails to satiate or regulate the behavior, reinforcing further binge episodes as individuals attempt to achieve the desired gratification. Over time, this dysregulation may further alter reward circuitry, akin to neuroadaptations seen in substance use disorders, where excessive engagement with the addictive stimuli leads to increased anticipatory salience and diminished hedonic impact. The repetitive engagement with binge eating behavior could thus perpetuate itself, as the neural imbalance strengthens and becomes more ingrained\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhile preclinical models of binge eating\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and neuroimaging studies on substance abuse\u003csup\u003e8\u003c/sup\u003e/food addiction\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e support the Addictive Appetite Model, human neuroimaging findings in BN and BED populations remain inconsistent. For instance, Bohon and Stice reported no significant differences in basal ganglia or orbitofrontal cortex (OFC) activation during food reward processing in women with BN compared to healthy controls (HC)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Conversely, Simon et al. observed heightened medial OFC responses to food receipt in individuals with BN and BED, a region implicated in encoding reward value\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. While it is likely that these discrepancies might reflect methodological differences in task design (Simon et al. lacks the granularity provided by separate anticipation and receipt phases) and sample characteristics, more targeted investigations to clarify how reward circuits are altered in BN and BED during anticipation and receipt of food rewards are paramount to further test the the Addictive Appetite model.\u003c/p\u003e \u003cp\u003eIntranasal oxytocin has emerged as a promising candidate for intervention in BN/BED. Oxytocin receptors are widely expressed in key regions implicated in reward and appetite regulation, including the NAcc, ventral tegmental area (VTA), and hypothalamus\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Oxytocin also exerts well-documented functional effects on reward processing, with relevance for appetite regulation\u003csup\u003e\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. For instance, oxytocin administration into the NAcc core suppresses both hunger-driven and palatable food intake in non-deprived animals\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, while also reducing methamphetamine-seeking behavior in rats\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, highlighting its broader influence on compulsive reward-driven behaviors. Clinically, intranasal oxytocin has demonstrated potential in reducing hedonic overeating\u003csup\u003e\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, including in BN\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. However, current evidence is inconsistent. For instance, our recent work found no significant effects of a divided 64IU dose on caloric consumption in BN/BED\u003csup\u003e25\u003c/sup\u003e. This highlights the need for further investigation into mechanisms of action as it is plausible that subtle effects of intranasal oxytocin on appetitive brain circuits may not reach full behavioral expression at the doses and time points measured in existing studies.\u003c/p\u003e \u003cp\u003eThe current study had two complementary aims: (1) to test the Addictive Appetite Mode\u003cb\u003el\u003c/b\u003e predictions in women with BN and BED, focusing on reward processing during the anticipation and receipt of palatable food; and (2) to evaluate the effects of intranasal oxytocin, exploring its therapeutic potential. Specifically, we hypothesized that women with BN and BED would show heightened blood oxygenation dependent (BOLD) functional magnetic resonance imaging (fMRI) response in the NAcc during palatable food anticipation but reduced response during palatable food receipt compared to controls. We further hypothesized that oxytocin would mitigate these differences. Exploratory whole-brain analyses were conducted to identify additional regions influenced by oxytocin or eating disorder status.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe recruited a total of 52 women through advertisements: 20 women met DSM-5 criteria for BN, 5 women met DSM-5 criteria for BED, and 27 women had no current or prior history of an eating disorder. Details regarding participants\u0026rsquo; demographic and clinical characteristics are presented in \u003cstrong\u003eTable 1\u003c/strong\u003e. Further details regarding the eligibility criteria and clinical profile of participants are presented in the Supplementary Material. Sample size was decided based on a priori power analysis implemented in G*Power\u003csup\u003e26\u003c/sup\u003e. This analysis estimated that a total sample size of 50 participants would be needed to detect a medium effect size (partial eta square of 0.04) in a 2-way within-between interaction with 80% power. Ethical approval for the study was granted by the London \u0026ndash; Camberwell St Giles Research Ethics Committee (Reference: 14/LO/2115).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis proof-of-concept study employed a double-blind, placebo-controlled, crossover design. Each participant was invited to come to the laboratory on three occasions. The first occasion was a preliminary screening visit in which each participant signed informed consent and was screened for eligibility for the study. Each participant was then given a link to an online survey in which they could provide basic demographic data (including age and education level) before the first experimental visit.\u003c/p\u003e\n\u003cp\u003eNext, participants attended two counterbalanced sessions (oxytocin/placebo) held two days apart to ensure drug washout and that each participant completed each of the experimental study sessions whilst in the same phase of the menstrual cycle. After fasting for 2.5 hours, they self-administered 40 IU oxytocin/placebo using a standard nasal spray. All sessions were conducted in the afternoon to avoid potential circadian confounds. The dose selection and route of administration were informed by previous evidence showing suppression of caloric intake in one study with BN patients\u003csup\u003e24\u003c/sup\u003e, and modulation of brain perfusion at rest in healthy men in another two studies\u003csup\u003e27, 28\u003c/sup\u003e. The full dose was administered over a series of 10 sprays, each administered 30 seconds apart, alternating nostrils each time following gold-standard recommendations\u003csup\u003e29\u003c/sup\u003e. The fMRI task subsequently commenced 23.16 (\u0026plusmn;4.46) minutes after the end of drug administration, on average.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003efMRI Scan Set-Up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach participant lay on the scanning bed with an \u003cstrong\u003eMRI-compatible flavor-dispensing box\u003c/strong\u003e (containing cold Evian water and Galaxy chocolate milk) positioned under their knees. A hose delivered the liquids through a disposable mouthpiece, secured with a plastic clamp on the head coil. Participants held a button box for responses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003efMRI Task\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore each fMRI run, participants rated the \u003cstrong\u003epleasantness, intensity, and anxiety\u003c/strong\u003e of \u003cstrong\u003e0.5 mL\u003c/strong\u003e of chocolate milk and water using a \u003cstrong\u003evisual analogue scale (VAS)\u003c/strong\u003e, responding via button presses. During the fMRI task (\u003cstrong\u003eFigure 1\u003c/strong\u003e), participants viewed images of a glass of chocolate milk or water for three seconds and indicated the image type using button presses. A fixation cross then appeared for a jittered interval of one to seven seconds. In valid trials, a \u003cstrong\u003e0.5 mL\u003c/strong\u003e squirt of the corresponding liquid was delivered through the mouthpiece, which participants held in their mouth for three seconds before being instructed to swallow following a jittered fixation cross lasting one to nine seconds. In invalid trials, no liquid was delivered, and the fixation cross remained on screen for an additional five seconds before the next trial began. Each run consisted of \u003cstrong\u003e50 trials (30 valid and 20 invalid trials)\u003c/strong\u003e, with 25 images of each stimulus, presented in a pseudo-randomized order. After the first valid trial, participants rated the pleasantness and intensity of the received liquid, repeating this every 10 valid trials. A second fMRI run followed the same procedure, with a newly randomized stimulus order.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003efMRI Scanning Protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe images were acquired using a \u003cstrong\u003e3.0 Tesla GE unit.\u003c/strong\u003e Each fMRI run lasted 14 minutes (422 volumes). Four dummy scans were acquired and discarded. Functional images were acquired with 41 slices (3mm thickness, 0.3mm gap, FOV = 240mm, 64\u0026times;64 matrix, voxel size = 3.75\u0026times;3.75\u0026times;3mm). The scan parameters were TE = 30ms, TR = 2000ms, and a 75\u0026deg; flip angle. A 3D high-spatial-resolution, magnetization prepared rapid acquisition T1-weighted scan (FOV of 270mm, TR/TE/TI = 7.31/3.02/400ms) was also acquired at the end of the session.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI data preprocessing and first-level modelling\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreprocessing:\u003c/strong\u003e We carried out the preprocessing using FEAT, as part of the FMRIB Software Library (FSL) v6.0. Best practice recommendations in taste-related neuroimaging\u003csup\u003e30\u003c/sup\u003e were followed which included: i) standard head motion correction by volume-realignment to the middle volume using MCFLIRT; ii) slice-time correction; iii) skull-stripping of both functional and structural images using the Brain Extraction Tool (BET); iv) denoising using Independent Component Analysis based Automated Removal of Motion Artifacts (ICA-AROMA); v) high-pass filter (0.01 Hz); vii) registration to high-resolution MPRAGE scans via a 6-parameter linear registration (FLIRT) and spatial normalization to the Montreal Neurological Institute (MNI) 152\u0026mdash;\u003cem\u003eT\u003c/em\u003e\u003csub\u003e1\u003c/sub\u003e 2-mm template via a 12-parameter nonlinear registration (FNIRT). Functional images were resampled into the standard space with 2-mm isotropic voxels and were smoothed with a Gaussian kernel of 6-mm full-width at half-maximum. All scans had mean frame-wise displacement \u0026lt; 0.25 mm and were therefore included for further analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFirst-level modelling:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe constructed a design matrix with separate regressors (duration = 0) for chocolate or water anticipation (for valid and invalid trials), chocolate or water receipt, the \u0026ldquo;Swallow\u0026rdquo; instruction, and VAS completion. Event timings were convolved with a canonical hemodynamic response function. We also included 24 head motion parameters (6 head motion parameters, 6 head motion parameters one time point before, and the 12 corresponding squared items) to model the residual effects of head motion as covariates of no interest \u0026ndash; this approach has been shown to more efficiently remove head motion effects from BOLD-fMRI data\u003csup\u003e31, 32\u003c/sup\u003e. We applied pre-whitening to remove residual temporal autocorrelation. The following contrasts at the single-subject level were generated using FSL\u0026rsquo;s FLAME\u003csup\u003e\u0026nbsp;\u003c/sup\u003ein mixed-effects mode: (1) chocolate versus water anticipation for both valid and invalid trials; and (2) chocolate versus water delivery. We excluded trials in which participants did not correctly indicate the presence of the chocolate milk image versus water image to ensure that we only included trials where participants paid attention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBehavioural ratings:\u0026nbsp;\u003c/strong\u003eFirst, we averaged ratings for each of the three VAS (hedonic, intensity and anxiety) for each participant, session and stimulus type. Then, we investigated the effects of stimulus, group, treatment, and all possible two- and three-way interactions using two-way mixed ANOVAs and respective Bayesian counterparts as implemented in JASP 0.8.5.1\u003csup\u003e33-38\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003efMRI\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegions-of-interest analyses:\u0026nbsp;\u003c/strong\u003eFor the contrast chocolate\u003csub\u003eanticipation\u003c/sub\u003e vs water\u003csub\u003eanticipation\u003c/sub\u003e,our ROI analyses were focused on our primary region, the nucleus accumbens, and five other regions: the midbrain, the putamen, the caudate nucleus, the pallidum and the amygdala (all bilateral). All these regions have been previously shown to be engaged during the anticipation of appetitive stimuli, including palatable food. For the contrast chocolate\u003csub\u003edelivery\u003c/sub\u003e vs water\u003csub\u003edelivery,\u0026nbsp;\u003c/sub\u003ewe focused on the above six regions plus the insula and the hypothalamus. The insula is part of the primary gustatory cortex and increases in the BOLD signal in the insula have been consistently reported in response to gustatory stimulation\u003csup\u003e10, 39\u003c/sup\u003e. The hypothalamus plays a pivotal role in food intake networks and increases in the BOLD signal in this region have been reported in response to glucose and palatable food (though inconsistently)\u003csup\u003e40-42\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eWe used anatomically defined masks to extract the median parameter estimate of all voxels within each ROI from the unsmoothed first-level contrasts using \u003cem\u003efslmeants\u003c/em\u003e. The masks were derived from a high-resolution probabilistic atlas of subcortical structures\u003csup\u003e43\u003c/sup\u003e by thresholding each map to include voxels with 50% probability or higher of belonging to a certain ROI and then binarizing the thresholded maps. The midbrain mask included both VTA and substantia nigra (SN). Since a large proportion of our participants had high levels of drop out of the BOLD signal in the nucleus accumbens\u003csup\u003e44\u003c/sup\u003e, we only extracted data from the voxels of this ROI that had less than 10% of BOLD signal loss in all scans. This allowed us to sample the same number of voxels in each participants/condition while discarding voxels where the BOLD signal could not be measured reliably. The final number of voxels in the nucleus \u003cem\u003eaccumbens\u003c/em\u003e ROI was 23.\u003c/p\u003e\n\u003cp\u003eWe investigated the effects of group, treatment, and group x treatment using two-way mixed ANOVAs. We also conducted exploratory analyses testing for Pearson correlations between parameter estimates reflecting changes in BOLD signal related to the delivery of chocolate and water and: i) hedonic, intensity and anxiety ratings during the task; ii) BMI, eating and affective symptom severity. As a measure of eating symptom severity, we used the global EDEQ scores. Since patients with BN/BED score highly on scales measuring anxiety, stress and depression, and scores on these scales were highly correlated with each other, we used within-group principal component analysis (PCA) on these three measures to obtain a single score reflecting affective/stress symptom severity. The first principal component accounted for 70.81% and 83.47% of the total variance in the patients and HCs, respectively. Correlations were calculated separately for BN/BED and HC participants.\u003c/p\u003e\n\u003cp\u003eIn all our analyses, we set statistical significance at p\u0026lt;0.05 (two-tailed), applying false-discovery rate (FDR) correction for the number of ROIs tested. Our Bayesian analyses used the uninformative priors specified as default in JASP. An increase in Bayes Factor (BF) in our analyses corresponds to an increase in evidence in favour of the alternative hypothesis. To interpret BF, we used the Lee and Wagenmakers\u0026rsquo; classification scheme\u003csup\u003e45\u003c/sup\u003e: BF \u0026lt; 1/10, strong evidence for the null hypothesis; 1/10\u0026lt;BF\u0026lt;1/3, moderate evidence for null hypothesis; 1/3 \u0026lt; BF \u0026lt; 1, anecdotal evidence for null hypothesis; BF \u0026gt; 1, anecdotal evidence for the alternative hypothesis; 3\u0026lt;BF\u0026lt;10, moderate evidence for the alternative hypothesis; BF \u0026gt; 10, strong evidence for the alternative hypothesis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhole-brain analyses:\u0026nbsp;\u003c/strong\u003eWe also conducted exploratory analyses at the whole-brain level. Using data from the placebo session of our HC group, we investigated main effects of tasks using one-sample T-tests. For the effects of group, treatment, and group x treatment, we took a partitioned errors approach to account for the likely violation of sphericity present in data from full within-subjects designs\u003csup\u003e46\u003c/sup\u003e. Briefly, to calculate the main effect of group, we averaged the first-level maps across treatment levels for each participant and then entered these average maps into an independent samples \u003cem\u003et\u003c/em\u003e-test. To calculate the main effect of treatment, we subtracted the first-level placebo maps from oxytocin maps and then entered these difference maps into a one-sample \u003cem\u003et\u003c/em\u003e-test pooling together HC and BN/BED patients. To calculate the group x treatment interaction, we entered the difference maps described above into an independent samples \u003cem\u003et\u003c/em\u003e-test. For all whole-brain analyses, we applied cluster-based inference within Randomise\u003csup\u003e41\u003c/sup\u003e (5000 permutations), considering a cluster significant if \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFWE\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, corrected for multiple comparisons using the null distribution of the maximum cluster size across the image.\u003c/p\u003e\n\u003cp\u003eAll statistical analyses (behavioural and fMRI data) were conducted with the researcher unblinded regarding treatment or group status.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eEffects of diagnosis, treatment and diagnosis x treatment on behavioural ratings of taste stimuli\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe found significant main effects of stimuli for all the three behavioural ratings (Table 2). Post hoc investigations of these effects revealed that chocolate milk was ranked as more palatable (T(47)=5.64, \u003cem\u003ep\u003csub\u003eTukey\u003c/sub\u003e\u003c/em\u003e \u0026lt; 0.001, d = 1.084), more intense (T(46)=5.83, \u003cem\u003ep\u003csub\u003eTukey\u003c/sub\u003e\u003c/em\u003e \u0026lt; 0.001, d = 1.408) and more anxiety-provoking (T(50)=2.50, \u003cem\u003ep\u003csub\u003eTukey\u003c/sub\u003e\u003c/em\u003e = 0.016, d = 0.346,) than water, across groups. We also found significant main effects of group for the hedonic and anxiety ratings. Women with BN/BED also rated both chocolate milk and water as less pleasant (T(47)=3.22, \u003cem\u003ep\u003csub\u003eTukey\u003c/sub\u003e\u003c/em\u003e=0.018, d= -0.349) and more anxiety-provoking (T(50)=3.74, \u003cem\u003ep\u003csub\u003eTukey\u003c/sub\u003e\u003c/em\u003e\u0026lt;0.001, d=0.519) than healthy women (Figure 2 and Table 2). None of the remaining effects reached significance; Bayesian analyses were consistent with frequentist analyses (Table 2). Repeating the same analyses but this time including age, BED diagnosis, BMI, phase of menstrual cycle, current medication or comorbidities as covariates of non-interest did not change the overall pattern of results (Supplementary Table S1).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMapping the BOLD responses during the anticipation and delivery of palatable stimuli in the healthy group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the placebo session, during the anticipation phase, observing the cue for chocolate milk as compared to the cue for water (chocolate\u003csub\u003eanticipation\u003c/sub\u003e vs water\u003csub\u003eanticipation\u003c/sub\u003e) was associated with i) increases in the BOLD signal in one cluster spanning the left precentral / postcentral gyri; ii) decreases in the BOLD signal in two clusters spanning the precentral gyrus and occipital cortex, respectively (Figure 3 and Supplementary Table S2). During the delivery phase, the receipt of chocolate milk as compared to the receipt of water (chocolate\u003csub\u003edelivery\u003c/sub\u003e vs water\u003csub\u003edelivery\u003c/sub\u003e) was associated with increases in the BOLD signal in nine clusters spanning the insula / central opercular cortex, cerebellum, and the precentral / postcentral gyri (all bilaterally) (Figure 3 and Supplementary Table S3). Contrary to expectation, we did not observe any changes in the BOLD signal in the basal ganglia or midbrain for either phase.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnosis, treatment and diagnosis x treatment effects on BOLD signal changes during palatable food anticipation and delivery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the contrast chocolate\u003csub\u003eanticipation\u003c/sub\u003e vs water\u003csub\u003eanticipation\u003c/sub\u003e,\u003csub\u003e\u0026nbsp;\u003c/sub\u003ewe did not find any significant\u003csub\u003e\u0026nbsp;\u003c/sub\u003eeffect of diagnosis, treatment, or diagnosis x treatment in any of the ROIs we tested (Table 3). For the contrast chocolate\u003csub\u003edelivery\u003c/sub\u003e vs water\u003csub\u003edelivery\u003c/sub\u003e,\u003csub\u003e\u0026nbsp;\u003c/sub\u003ewe found a significant main effect of diagnosis for the insula ROI, and a significant main effect of treatment for the hypothalamus ROI. None of the remaining effects reached significance (Table 4). As shown in Figure 4, the main effect of group in the insula was driven by an increased BOLD response to chocolate milk (but not water) in women with BN/BED as compared to HCs. The main effect of treatment in the hypothalamus was driven by a decrease in the BOLD response to chocolate milk (but not to water) for oxytocin, compared to placebo, across all participants (Figure 4). Results from Bayesian analyses were consistent with frequentist analyses of the same data (Table 3). Repeating the same analyses including age, BED diagnosis, BMI, phase of menstrual cycle, current medication, or comorbidities as covariates of non-interest did not change the overall pattern of results for the insula ROI; however, for the hypothalamus ROI, the main effect of treatment was no longer significant after FDR correction (Supplementary Tables S4 and S5).\u003c/p\u003e\n\u003cp\u003eWe also performed exploratory whole-brain analyses investigating effects of diagnosis, treatment and diagnosis x treatment beyond our pre-selected ROIs but no cluster survived correction for multiple comparisons.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelations between BOLD signal changes during delivery of palatable stimuli and behavioural ratings or clinical symptoms\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo help us interpret the potential functional relevance of the diagnosis-related changes in the insula BOLD response to the delivery of taste stimuli, we then sought to investigate whether contrast parameter estimates could predict: i) the behavioral ratings of pleasantness, intensity or anxiety-provoking of the taste stimuli; ii) clinical symptoms (including eating and general psychopathology) and BMI. We did not find any significant correlations in women with BN/BED or HCs (Supplementary Tables S6 and S7). Bayesian correlations were consistent with their frequentist counterparts.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eContrary to our hypotheses we did not observe any significant group differences in NAcc BOLD signal changes during the anticipation or receipt of palatable stimuli. Furthermore, we did not observe any modulatory effect of intranasal oxytocin in this region. In contrast, we observed heightened insula activation in BN/BED participants during the receipt of the palatable stimulus (chocolate milk), consistent with altered sensory and interoceptive processing of palatable stimuli. Oxytocin suppressed hypothalamic responses to palatable stimuli across both groups but did not significantly influence behavioural ratings or insula activity. Altogether, our main findings highlight that binge eating behaviours may involve neural pathways beyond traditional reward circuitry and suggest a potential homeostatic mechanism by which OT may influence appetite regulation, strengthening the rationale for future larger dose-response studies examining its therapeutic potential and optimal dose in BN/BED.\u003c/p\u003e \u003cp\u003eThe absence of significant group differences in the NAcc during food anticipation or delivery challenges key predictions of the Addictive Appetite Model. This model proposes that BN/BED is characterized by heightened reward anticipation and blunted reward receipt, yet our results indicate minimal involvement of these pathways. Importantly, this lack of group differences cannot be attributed to a failure of BN/BED participants to perceive the stimuli as rewarding. Both groups rated chocolate milk as pleasant, indicating that the stimuli were salient and hedonic. However, the pleasantness ratings did not translate into robust NAcc activation, raising questions about the ability of the task to elicit strong reward responses. Notably, HCs also showed minimal engagement of the NAcc, further suggesting that the experimental paradigm may not have been optimized to activate reward circuits in either group. Factors such as the controlled laboratory setting, the modest volume of chocolate milk delivered (though similar to other studies\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e), the fat content of the stimuli (as participants might consider foods higher in fat as more rewarding), the satiety state, and the repetitive nature of the task may have attenuated the motivational and hedonic responses to our palatable stimuli\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. However, we also note the substantial dropout of BOLD signal in the NAcc\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e, which might have limited statistical power to detect any group or treatment effects if they existed, as we could only sample a small percentage of voxels within this region. While not uncommon in standard acquisitions as ours, this is a methodological aspect future studies should consider, for instance, by attempting to minimise dropout by adjusting the angle of acquisition to maximise coverage of the NAcc and orbitofrontal cortex\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe note though that our null findings for the NAcc largely align with previous studies of women with current BN or a history of BN, which also failed to observe differences in BOLD activation in the ventral striatum in response to receipt of expected sweet taste, as compared to control participants\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. One study serves as an exception that instead found heightened BOLD response in the left anterior ventral striatum amongst women with BN, as compared to HC, in response to unsweetened cream versus water\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. It may, therefore, be the case that disorder-related differences in the degree to which the ventral striatum is recruited during taste stimulation are specific to unsweetened high-fat stimuli, rather than sweet palatable tastes. Nevertheless, on balance, the evidence to date does not support differences in ventral striatum BOLD activation in response to sweet tastes in women with BN versus HC.\u003c/p\u003e \u003cp\u003eAt the behavioural level, women with BN/BED rated both chocolate and water tastes to be less pleasant, but more anxiety provoking compared to HC ratings, which one might reasonably expect be associated with detectable differences in BOLD response\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. The decreased pleasantness ratings for the chocolate milk align well with our predictions but the decrease for the water stimuli was unexpected but not implausible if interpreted in the wider context of the emotional relationship BN/BED patients establish with food. Indeed, BN/BED is often accompanied by heightened negative emotionalityparticularly in situations involving food or related stimuli\u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e. This pervasive negative emotional context could influence the evaluation of both palatable and neutral stimuli, reflecting a general difficulty in experiencing neutral or positive responses to sensory food stimuli\u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn contrast to the null findings observed for the ventral striatum, we did observe a greater chocolate-versus-water BOLD contrast in the insula amongst women with BN/BED versus healthy comparison women. These findings concur with previous neuroimaging studies in BN, which have repeatedly reported differences in activation of the insula in response to gustatory stimulation\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. The mid-insula acts as the primary taste cortex, and the anterior insula plays an important role in the integration gustatory stimuli with information about the texture and temperature of food stimuli\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. Thus, this finding is compatible with an interpretation of group differences in primary processing of food stimuli, although this is by no means the only explanation for our observations. Neural activity of the insula is also associated with a wide range of other cognitive and emotional processes, including craving\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e and disgust\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. Therefore, in the absence of significant correlations between insula responses and any of our behavioural ratings or symptoms, it is likely that differences in the insula responses reflect mostly implicit processes that do not reach conscious perceptions. One such process might be interoception, as the insula is also a key hub for interoceptive processing\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e, which involves the perception and interpretation of internal bodily states such as hunger, fullness, and the sensory experience of eating\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. Within the Predictive Coding Model, the insula plays a critical role in computing interoceptive prediction errors\u0026mdash;comparing expected bodily sensations (e.g., the anticipated fullness from food) with actual sensory input \u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e. In BN/BED, prediction errors may be miscalibrated, leading to exaggerated sensory-emotional responses to food consumption. For individuals with BN/BED, this hyperactivation may make the sensory experience of eating palatable foods more salient, potentially contributing to loss of control over eating. Such findings align with previous work indicating that individuals with BN/BED exhibit impaired interoceptive awareness and greater reliance on external cues rather than internal satiety signals to regulate eating behavior\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn contrast with our predictions, intranasal oxytocin did not modulate BOLD responses to palatable taste anticipation and delivery in the ventral striatum. Previous evidence from animal studies has supported an anorexigenic neural pathway from oxytocinergic neurons in the paraventricular nucleus of the hypothalamus, which suppress the activity of dopaminergic neurons in the ventral tegmental area, ultimately inhibiting the activity of neurons in the NAcc which underpin reward-related feeding\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e. However, the lack of oxytonergic effects in the current study may be due to insufficient engagement of the NAcc during the task, limiting the ability to detect modulation by oxytocin. Instead, the only drug difference observed was in the hypothalamus. Visual inspection of the data revealed that this difference was largely driven by oxytocin-induced suppression of BOLD response to chocolate taste, which did not occur in response to water. This finding partially corresponds with van der Klaauw et al.\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e, who reported that oxytocin suppresses BOLD response within the hypothalamus in response to visual food stimuli in a mixed sample of men and women. However, the lack of oxytocin effects on behavioural ratings suggests that these neural changes may not immediately translate into observable shifts in appetite or eating behaviour, at least under controlled experimental conditions. It is possible though that this finding may have functional significance for eating behaviour. For example, previous work has highlighted that the anorectic effects of the anti-obesity drug sibutramine are likely mediated by suppression of hypothalamic response to visual food stimuli\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e. This underscores the need to explore alternative dosing regimens or contexts where oxytocin\u0026rsquo;s effects may be more pronounced.\u003c/p\u003e \u003cp\u003eThis study has several strengths that enhance the reliability and generalizability of the findings. First, the robust double-blind, crossover design minimizes biases and individual variability, providing a high degree of control over potential confounding factors. Second, the inclusion of participants with comorbidities\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e and those on psychoactive medications\u003csup\u003e\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e reflects the real-world clinical population of individuals with BN and BED, increasing the ecological validity of the results. Third, we applied a data-driven approach to denoise the BOLD signal, which boosts signal-to-noise ratio. We also complemented the standard frequentist analyses with Bayesian analyses, which allowed a more insightful interpretation of our null findings as reflective of lack of group and treatment effects given the data. However, our study was not without limitations.\u003c/p\u003e \u003cp\u003eFirst, the conditional effect of oxytocin on BOLD response in the NAcc might have been greater at an alternative time frame or dose of administration. Indeed, we chose the current dose of 40IU based on previous evidence from our own lab indicating that this dose effectively reduces neural activation in regions of interest, particularly within the basal ganglia in healthy men\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. However, the latest evidence from the current participant sample failed to replicate effects of oxytocin on cerebral blood flow in women at the same dose and time frame of administration\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e, and two other studies from our research team suggest that lower doses might in fact be more effective in modulation brain responses in the amygdala at rest \u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e and midbrain \u0026ndash; subgenual anterior cingulate circuitry during prosocial learning\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e. It is, therefore, possible that more pronounced changes in BOLD response might be observed to the anticipation and receipt of palatable taste following lower doses of intranasal oxytocin, as compared to the 40IU dose used in the current study. We also included women across different stages of the menstrual cycle (though each woman was tested at the same phase of the cycle for OT and placebo), including some women taking hormonal contraception, due to the practical challenges associated with recruiting an adequate sample of women with BN or BED. While this decision may improve ecological validity due to the recruitment of a more representative sample of British women, previous research has found that hormonal contraception can blunt the effects of oxytocin on reward processing\u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOverall, our work underscores the importance of expanding theoretical frameworks for BN and BED to include sensory and interoceptive processes alongside reward dysregulation. It also suggests a potential mechanism by which oxytocin may influence appetite regulation, strengthening the rationale for future larger dose-response studies examining its therapeutic potential and optimal dose in BN/BED.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e Nothing to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eML was supported by grants from the Swiss Fund for Anorexia Nervosa, the Guy\u0026rsquo;s and St Thomas\u0026rsquo; NHS Foundation Trust, and a King\u0026rsquo;s Health Partners Challenge Fund. YP was supported by an Economic and Social Research Council fellowship (grant number ES/K009400/1). JT, OD and DM were supported by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King\u0026apos;s College London. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT author statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDM\u003cstrong\u003e:\u003c/strong\u003e data curation (equal), formal analysis (lead), visualisation (lead), writing (original draft) (equal), writing (review and editing) (equal).\u003c/p\u003e\n\u003cp\u003eML: data curation (equal), formal analysis (supporting), investigation (lead), project administration (lead), writing (original draft) (equal), writing (review and editing) (supporting).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOD: formal analysis (supporting).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJL: conceptualisation (supporting), writing (review and editing) (supporting).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJT: conceptualisation (equal), supervision (equal), funding acquisition (lead), writing (review and editing) (supporting).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYP: conceptualisation (equal), supervision (equal), funding acquisition (supporting), writing (review and editing) (equal). \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKahn DA, Reviewed b. 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Oxytocin modulates neurocomputational mechanisms underlying prosocial reinforcement learning. \u003cem\u003eProg Neurobiol\u003c/em\u003e 2022; \u003cstrong\u003e213: \u003c/strong\u003e102253.\u003c/li\u003e\n\u003cli\u003eScheele D, Plota J, Stoffel-Wagner B, Maier W, Hurlemann R. Hormonal contraceptives suppress oxytocin-induced brain reward responses to the partner\u0026apos;s face. \u003cem\u003eSoc Cogn Affect Neurosci\u003c/em\u003e 2016; \u003cstrong\u003e11\u003c/strong\u003e(5)\u003cstrong\u003e: \u003c/strong\u003e767-774.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Descriptive demographic and clinical data.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHealthy Control (\u003cem\u003en\u003c/em\u003e = 27)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBN/BED (\u003cem\u003en\u003c/em\u003e = 25)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIQR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIQR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e23.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e5.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e23.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e9.75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e22.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e23.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e3.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eRQF Education Level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eGlobal EDE-Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e4.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eEDE-Q Restraint\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e4.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eEDE-Q Eating Concern\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e4.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eEDE-Q Weight Concern\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e4.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eEDE-Q Shape Concern\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e5.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1.63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eDASS - Depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e24.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e15.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eDASS - Anxiety\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e10.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e12.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003eDASS - Stress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e6.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e20.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e18.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote. BN = bulimia nervosa; BED = binge eating disorder; IQR = interquartile range; BMI = body mass index; RQF = Regulated Qualifications Framework.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Effects of stimuli, diagnosis, treatment and respective interactions on pleasantness, intensity, and anxiety ratings of taste stimuli.\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHedonic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntensity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnxiety\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF(1, 206)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBF\u003csub\u003e01\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF(1,207)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBF\u003csub\u003e01\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF(1,207)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBF\u003csub\u003e01\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e5.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4.237\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.841\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.364\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.288\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e14.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e43.295\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.864\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.287\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.615\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.027\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.546\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eStimuli\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e57.572\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8.69x10\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e95.201\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e1.18x10\u003csup\u003e30\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e6.234\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e2.154\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eDiagnosis x Treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.733\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.572\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.453\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.929\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.296\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eDiagnosis x Stimuli\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.907\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.152\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.462\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e1.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.483\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.490\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.210\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eStimuli x Treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.847\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.931\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.401\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.529\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.183\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003eDiagnosis x Treatment x Stimuli\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e2.127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.151\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.419\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.628\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.432\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0.277\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.243\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.624\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.323\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Effects of diagnosis, treatment and diagnosis x treatment on BOLD responses during anticipation of palatable as compared to tasteless stimuli.\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMain effect diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMain effect treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInteraction diagnosis x treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF(1,103)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBF\u003csub\u003e01\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF(1,103)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBF\u003csub\u003e01\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF(1,103)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBF\u003csub\u003e01\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eNucleus Accumbens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.923\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.174\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e1.168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.285\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.767\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.277\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.677\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eMidbrain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.268\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.607\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.183\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.052\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.821\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.821\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.822\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eCaudate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.861\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.169\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.215\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.645\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.774\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.167\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.776\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.383\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003ePutamen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.183\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.633\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.430\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.767\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003ePallidum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.891\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.713\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.402\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.767\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.218\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e1.329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.254\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eAmygdala\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.923\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.169\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.511\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.767\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.183\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.932\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Effects of diagnosis, treatment and diagnosis x treatment on BOLD responses during delivery of palatable as compared to tasteless stimuli.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMain effect diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMain effect treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInteraction diagnosis x treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF(1,103)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBF\u003csub\u003e01\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF(1,103)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBF\u003csub\u003e01\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eF(1,103)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBF\u003csub\u003e01\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003eNucleus Accumbens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.796\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.928\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.178\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.207\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.651\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.856\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.281\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.599\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.858\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003eMidbrain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e1.240\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.875\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.269\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.856\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.856\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.458\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n 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Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6207163/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6207163/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003eBulimia nervosa (BN) and binge eating disorder (BED) are marked by recurrent episodes of binge-eating despite negative consequences. Although dysregulated reward processing has been proposed as a key mechanism, experimental evidence has been inconsistent. Intranasal oxytocin (OT), a neuropeptide involved in reward modulation and appetite regulation has been suggested as a potential treatment; however, its neurobiological effects remain unclear. This study examined brain responses during palatable food anticipation and consumption in BN/BED patients versus healthy controls and evaluated OT’s modulatory impact.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In a randomized, double-blind, placebo-controlled, crossover fMRI study, 24 women with BN/BED and 23 healthy controls received 40 IU of intranasal OT or placebo prior to scanning. During fMRI, participants experienced both anticipation and receipt of palatable (chocolate milk) and neutral (water) stimuli while providing subjective ratings of pleasantness, intensity, and anxiety. Effects of diagnosis, treatment, and their interaction were analyzed using both frequentist and Bayesian methods.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Compared with controls, BN/BED participants rated both stimuli as less pleasant and more anxiety-provoking. fMRI revealed significantly greater insula activation during palatable food receipt in BN/BED. In contrast, nucleus accumbens activity did not differ between groups. OT suppressed hypothalamic responses to palatable taste across groups, without significantly affecting behavioral ratings or other regions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e These findings challenge the view that binge eating is solely driven by reward dysfunction and highlight a potential role for altered sensory/interoceptive processing in BN/BED. Although OT modulated hypothalamic activity, its broader clinical utility remains uncertain, warranting further dose-response studies to determine clinical efficacy.\u003c/p\u003e","manuscriptTitle":"Brain Responses during Anticipation and Consumption of Palatable Food in Women with and without Bulimia Nervosa or Binge Eating Disorder: disorder-related changes and modulation by intranasal oxytocin","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 06:43:30","doi":"10.21203/rs.3.rs-6207163/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"transferred","content":"Translational Psychiatry","date":"2026-04-10T13:05:25+00:00","index":"","fulltext":""},{"type":"decision","content":"Reject after peer review","date":"2025-11-07T18:24:28+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-11-04T17:15:12+00:00","index":5,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-10-26T16:49:50+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-10-25T10:25:45+00:00","index":4,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-10-20T08:54:59+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-10-16T20:57:22+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-10-06T11:19:09+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-07-29T15:30:14+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-07-25T16:52:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-18T09:47:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-13T11:40:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Psychiatry","date":"2025-03-12T13:56:21+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2025-03-12T11:00:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"789d1f28-0a20-44aa-bd7c-820816e79392","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":45931052,"name":"Health sciences/Diseases/Psychiatric disorders"},{"id":45931053,"name":"Biological sciences/Drug discovery"}],"tags":[],"updatedAt":"2026-04-15T00:55:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-07 06:43:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6207163","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6207163","identity":"rs-6207163","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}