Prefrontal Responses during Proactive and Reactive Inhibition Are Differentially Impacted by Stress in Anorexia and Bulimia Nervosa

Abstract

Binge eating is a distressing, transdiagnostic eating disorder symptom associated with impulsivity, particularly in negative mood states. Neuroimaging studies of bulimia nervosa (BN) report reduced activity in frontostriatal regions implicated in self-regulatory control, and an influential theory posits that binge eating results from self-regulation failures under stress. However, there is no direct evidence that psychological stress impairs self-regulation in binge-eating disorders, or that any such self-regulatory deficits generalize to binge eating in underweight individuals (i.e., anorexia nervosa bingeing/purging subtype; AN-BP). We therefore determined the effect of acute stress on inhibitory control in 85 women (BN, 33 women; AN-BP, 22 women; 30 control participants). Participants underwent repeated functional MRI scanning during performance of the Stop-signal anticipation task, a validated measure of proactive (i.e., anticipation of stopping) and reactive (outright stopping) inhibition. Neural and behavioral responses to induced stress and a control task were evaluated on 2 consecutive days. Women with BN had reduced proactive inhibition, while prefrontal responses were increased in both AN-BP and BN. Reactive inhibition was neurally and behaviorally intact in both diagnostic groups. Both AN-BP and BN groups showed distinct stress-induced changes in inferior and superior frontal activity during both proactive and reactive inhibition. However, task performance was unaffected by stress. These results offer novel evidence of reduced proactive inhibition in BN, yet inhibitory control deficits did not generalize to AN-BP. Our findings identify intriguing alterations of stress responses and inhibitory function associated with binge eating, but they counsel against stress-induced failures of inhibitory control as a comprehensive explanation for loss-of-control eating.SIGNIFICANCE STATEMENT Binge eating is a common psychiatric syndrome that feels uncontrollable to the sufferer. Theoretically, it has been related to reduced self-regulation under stress, but there remains no direct evidence for this link in binge-eating disorders. Here, we examined how experimentally induced stress affected response inhibition in control participants and women with anorexia nervosa and bulimia nervosa. Participants underwent repeated brain scanning under stressful and neutral conditions. Although patient groups had intact action cancellation, the slowing of motor responses was impaired in bulimia nervosa, even when the likelihood of having to stop increased. Stress altered brain responses for both forms of inhibition in both groups, yet performance remained unimpaired. These findings counsel against a simple model of stress-induced disinhibition as an adequate explanation for binge eating.

Figure 1.

Overview of study design and Stop-signal anticipation task. A, Diagram of inpatient study protocol with representative timeline. Participants were randomized to either a stress induction or control task on each day, which was completed in the MR scanner. Created with BioRender.com. See Extended Data Figure 1-1 for plasma cortisol responses (percentage change from baseline) to the stress and control tasks. B, Participant ratings of subjective stress and electrical stimulation. The stress manipulation induced a significantly greater change in subjective stress compared with the neutral task. Participants rated the electrical stimulation as more painful, intense, and unpleasant following stress as compared with the control task, where stimulation was intended to be detectable but not unpleasant (Westwater et al., 2020). Ratings did not differ significantly by group (all p values >0.05). Error bars indicate the SEM. C, Schematic of SSAT trial types adapted from Zandbelt and Vink (2010). Left, On Go-signal trials, participants were instructed to respond when a moving bar reached the middle line. The target response time was 800 ms on each 1000 ms trial (1000 ms intertrial interval). Middle, A minority of trials (25%) were Stop-signal trials, where the moving bar stopped automatically before reaching the middle line. Participants were instructed to withhold their response in the event of a Stop-signal. Right, To index proactive inhibition, the probability of a Stop-signal occurring on a given trial ranged from 0% to 33%, as indicated by colored cues. Participants were told that Stop-signals would never occur on green (baseline) trials, but the likelihood of a Stop-signal occurring increased across yellow to red trials.

Figure 2.

Region of interest analyses identify altered inferior frontal and premotor activity during proactive inhibition in anorexia and bulimia nervosa. A, ROI analyses were conducted in eight regions that have previously been associated with proactive and reactive inhibition (Zandbelt et al., 2011; van Belle et al., 2014), as follows: right putamen (1), right opercular inferior frontal gyrus (2), right ventral inferior frontal gyrus (3), bilateral pregenual anterior cingulate cortex (4), bilateral caudate (5), bilateral superior parietal cortices (6), left premotor cortex (7), and right pre-supplementary motor cortex (8). Blue regions were used in the analysis of both proactive and reactive inhibition, whereas pink and red regions were unique to proactive and reactive analyses, respectively. ROIs are displayed in neurological orientation (L, left). B, The parametric effect of Stop-signal probability was related to increased right inferior frontal gyrus (pars opercularis) activity in the AN-BP group relative to control participants (p = 0.005). C, A three-way interaction indicated that the parametric effect of reaction time was related to decreased left premotor activity in the BN group compared with control participants following the stress induction (p < 0.001).

Figure 3.

Whole-brain activation in women with anorexia nervosa and bulimia nervosa, and control participants during the Stop-signal anticipation task. A–D, Two-sample t tests of the parametric effect of Stop-signal probability versus the implicit baseline (i.e., Go_0% trials; A), the parametric effect of reaction time versus the implicit baseline (B), successful Stop-signal versus the implicit baseline (C), and successful Stop-signal versus failed Stop-signal activation for AN-BP, BN, and control groups (D). A and B represent proactive inhibition contrasts, whereas C and D relate to reactive inhibition. Maps represent significant clusters (voxelwise p value < 0.001, FWE cluster probability p value < 0.05) and are presented in neurological orientation (L, left). For details on cluster size, coordinates, and associated test statistics, see Extended Data Figures 3-1, 3-2 3-3, 3-4.

Figure 4.

Impaired proactive inhibition in bulimia nervosa is associated with increased superior frontal gyrus activity. A, Reaction time increased as a function of Stop-signal probability in all groups; however, a significant group-by-probability interaction showed that women with BN did not slow to the same degree as control participants in response to increasing Stop-signal probability (p = 0.003). B, C, This impairment in proactive inhibition was associated with greater activity in the left superior frontal gyrus (k = 25 voxels, z = 4.58, MNI_X,Y,Z = −23, 33, 54; cluster-defining threshold, p < 0.001; FWE-corrected cluster probability, p < 0.05) in BN relative to control participants. C, A three-way interaction was related to stress-induced increases in the right superior frontal gyrus in women with BN relative to those with AN-BP (k = 34 voxels, z = 4.52, MNI_X,Y,Z = 22, 54, 36; cluster-defining threshold, p < 0.001; FWE-corrected cluster probability, p < 0.05). The size, coordinates, and test statistics of significant clusters from the whole-brain linear mixed-effects analysis of proactive inhibition are reported in Extended Data Figure 4-1. Results are displayed in neurological orientation (L, left). Individual values are overlaid on the mean modulated percentage signal change by group. Error bars indicate the SEM.

Figure 5.

Stress reduces right ventromedial prefrontal cortex activity in women with anorexia nervosa (binge/purge subtype) during reactive inhibition. A, A significant three-way interaction indicated that right vmPFC activity was significantly reduced following acute stress compared with the neutral condition in the AN-BP group relative to the control group (k = 32 voxels, z = −4.19, MNI_X,Y,Z = 4, 45, −9; cluster-defining threshold, p < 0.001; FWE-corrected cluster probability, p < 0.05). The size, coordinates, and test statistics of significant clusters from the whole-brain linear mixed-effects analysis of reactive inhibition are reported in Extended Data Figure 5-1. B, Change in the average percentage signal change for the vmPFC cluster from preinduction to postinduction across conditions. Individual values are overlaid on the mean change in percentage signal change (post – pre) by group.

Figure 6.

Associations between prefrontal responses during inhibition and ad libitum consumption. A, Greater vmPFC responses during reactive inhibition (Successful Stop vs Failed Stop) were negatively related to food consumption during the free-choice meal. For the contents of the meal and corresponding macronutrient information, see Extended Data Figure 6-1. B, Increased left superior frontal gyrus responses to greater Stop-signal probability were positively associated with food intake. Observations within the same participant are modeled with a line of best fit that reflects the overall brain–behavior association. While effects were derived from linear mixed-effects models, repeated-measures correlations were computed for visualization, using the rmcorr R package (Bakdash and Marusich, 2017).