Depression-Related Increases and Decreases in Appetite: Dissociable Patterns of Aberrant Activity in Reward and Interoceptive Neurocircuitry

Abstract

Objective: Appetite and weight changes are common but variable diagnostic markers in major depressive disorder: some depressed individuals manifest increased appetite, while others lose their appetite. Many of the brain regions implicated in appetitive responses to food have also been implicated in depression. It is thus remarkable that there exists no published research comparing the neural responses to food stimuli of depressed patients with increased versus decreased appetites.

Method: Using functional MRI, brain activity was compared in unmedicated depressed patients with increased or decreased appetite and healthy control subjects while viewing photographs of food and nonfood objects. The authors also measured how resting-state functional connectivity related to subjects' food pleasantness ratings.

Results: Within putative reward regions, depressed participants with increased appetites exhibited greater hemodynamic activity to food stimuli than both those reporting appetite decreases and healthy control subjects. In contrast, depressed subjects experiencing appetite loss exhibited hypoactivation within a region of the mid-insula implicated in interoception, with no difference observed in this region between healthy subjects and those with depression-related appetite increases. Mid-insula activity was negatively correlated with food pleasantness ratings of depressed participants with increased appetites, and its functional connectivity to reward circuitry was positively correlated with food pleasantness ratings.

Conclusions: Depression-related increases in appetite are associated with hyperactivation of putative mesocorticolimbic reward circuitry, while depression-related appetite loss is associated with hypoactivation of insular regions that support monitoring the body's physiological state. Importantly, the interactions among these regions also contribute to individual differences in the depression-related appetite changes.

Figure 1. Depression-related increases and decreases in appetite are associated with differential insula and orbitofrontal cortex responses in regions that respond more to food images in healthy control subjects

The brain images show seven regions where activity was greater in response to food than non-food pictures in the healthy non-depressed subjects (p <0.05 corrected). The bar graphs show the mean response for each depressed group within regions-of-interest defined using only the image data from the healthy control group. Significant differences were observed between the depressed groups in the bilateral insula and left orbitofrontal cortex regions of interest. Brain slice coordinates conform to the stereotaxic array of Talairach and Tournoux (1988), with slices presented according to neurological convention (i.e., left hemisphere presented in left side of the image). The y-axis of each graph displays the fMRI percent signal change for food relative to non-food images. Error bars are not displayed for the healthy comparison subjects’ graphs as these subjects’ data were used to define the clusters, and therefore their variance estimate is overdetermined, and thus these data should not be compared statistically to the data from the other two groups.

Figure 2. One-way ANOVA: Regions exhibiting group differences in responses to food pictures

Statistical maps showing 11 brain regions where activity differed between the three groups (p < .05 corrected). Slice coordinates conform to the stereotaxic array of Talairach and Tournoux (1988), in which each plane is located by its distance in mm from the origin (anterior commissure), such that positive x, y and z correspond to left, anterior and dorsal, respectively. The left hemisphere is presented in the reader’s left. See Table S5 and Figure 3 for tests of the simple effects and effect sizes underlying these ANOVA main effects. Ant: Anterior; Post: Posterior; Vent: Ventral

Figure 3. Bar graphs demonstrating simple effects within the 11 clusters identified in the between-groups ANOVA

The bar graphs show the mean response (beta value) and simple effects for each group within the clusters identified in the whole-brain ANOVA to assess for group differences in responses to food pictures. Three general patterns emerged from the data. Within canonical reward-related regions (graphs against red background), depressed participants with increased appetites exhibited greater activity to food stimuli than both those reporting appetite decreases and healthy comparison subjects. In contrast, depression with appetite loss was associated with hypoactivation within a region of the mid-insular cortex previously implicated in interoceptive and homeostatic signaling (graphs against blue background). Activity in the anterior insula exhibits a more graded response across the three groups. The y-axis of each graph displays the fMRI percent signal change for food images relative to non-food images.

Figure 4. Mid-insula Activity and Food Pleasantness Ratings

Depressed subjects with increased appetite exhibited a significant (p<.05) negative correlation between how highly they rated the anticipated pleasantness of food pictures in the Food Pleasantness Task and insula activity to food pictures (relative to non-food pictures) during the Food/nonfood Picture Task.

Figure 5. Resting-state functional connectivity between the mid-insula and putative reward regions is correlated with ratings of anticipated food pleasantness

Subjects’ anticipated food pleasantness ratings were positively correlated with the resting-state (intrinsic) functional connectivity between multiple regions within putative reward neurocircuitry and the left and right mid-insula ROI seed region defined in the healthy control subjects. Both mid-insula seed regions exhibited greater activity in response to food than non-food pictures in the healthy non-depressed subjects in the Food/non-food picture task, and also exhibited a significant negative correlation between food picture activity and pleasantness ratings in the MDD-increase groups.