Association of body mass and brain activation during gastric distention: implications for obesity

Abstract

Background: Gastric distention (GD), as it occurs during meal ingestion, signals a full stomach and it is one of the key mechanisms controlling food intake. Previous studies on GD showed lower activation of the amygdala for subjects with higher body mass index (BMI). Since obese subjects have dopaminergic deficits that correlate negatively with BMI and the amygdala is innervated by dopamine neurons, we hypothesized that BMI would correlate negatively with activation not just in the amygdala but also in other dopaminergic brain regions (midbrain and hypothalamus).

Methodology/principal findings: We used functional magnetic resonance imaging (fMRI) to evaluate brain activation during GD in 24 healthy subjects with BMI range of 20-39 kg/m(2). Using multiple regression and cross-correlation analyses based on a family-wise error corrected threshold P = 0.05, we show that during slow GD to maximum volumes of 500 ml and 700 ml subjects with increased BMI had increased activation in cerebellum and left posterior insula, and decreased activation of dopaminergic (amygdala, midbrain, hypothalamus, thalamus) and serotonergic (pons) brain regions and anterior insula, regions that were functionally interconnected with one another.

Conclusions: The negative correlation between BMI and BOLD responses to gastric distention in dopaminergic (midbrain, hypothalamus, amygdala, thalamus) and serotonergic (pons) brain regions is consistent with disruption of dopaminergic and serotonergic signaling in obesity. In contrast the positive correlation between BMI and BOLD responses in posterior insula and cerebellum suggests an opposing mechanism that promotes food intake in obese subjects that may underlie their ability to consume at once large food volumes despite increasing gastric distention.

Figure 1. Gradual gastric distention (GD) paradigm.

The deflated balloon was inserted orally and positioned in the stomach 2-cm above the gastro-esophageal junction. The solid and dashed lines depict the emptied (0 ml) and filled (500 ml for GD1 or 700 ml for GD2) balloon conditions. The balloon was filled and emptied with constant flow (5 ml/s) of tap water (warmed at 37°C) in either 90s to 500 ml (GD1) or in 140 s to 700 ml (GD2). The vagus nerve transmits the signal of a full stomach to the solitary and parabrachial nuclei in the brain stem that project to dopaminergic and serotonergic nuclei in midbrain and pons. Other regions implicated in the control of food intake are additionally highlighted (hypothalamus, amygdala, and cerebellum).

Figure 2. Behavioral responses during gradual GD.

Ratings of fullness, discomfort, hunger, and desire for food, collected during the empty and full balloon conditions for GD1 (500 ml) and GD2 (700 ml). (*) P<0.0002.

Figure 3. Brain activation during gradual gastric distention (GD).

Top panel: Statistical maps showing regions with significant brain activation (red-yellow) and deactivation (blue-green) during gradual GD. Bottom panel: correlations between BMI and BOLD-fMRI responses in the brain during gradual GD. Threshold for statistical significance: P _corr<0.05 corrected for multiple comparisons using the family-wise error (FWE) correction. Sample: 24 healthy controls. Data from all 47 GD1 and 43 GD2 fMRI runs were included in SPM2 multiple regression analyses. Activation/correlation patterns reflecting the effect of volume were not significant in any brain region.

Figure 4. BOLD signals in hyper-activated regions vs. BMI.

Scatter plots exemplifying the positive correlations between the body mass index (BMI) and the average BOLD-fMRI response across all volumetric conditions (125, 375, 500, 600, and 700 ml) in cerebellum and posterior insula during gradual GD (N = 24).

Figure 5. BOLD signals in hypo-activated regions vs. BMI.

Scatter plots exemplifying the negative correlations between BMI and the average BOLD-fMRI responses across all volumetric conditions (125, 375, 500, 600, and 700 ml) in dopaminergic brain regions (hypothalamus, midbrain, and amygdala) during gradual GD (N = 24).

Figure 6. Association of BOLD signals in hyper- and hypo-activated regions.

Regression plots exemplifying positive and negative cross-correlations of BOLD-fMRI signals (averaged across all volumetric conditions; 125, 375, 500, 600, and 700 ml) in different ROIs (listed in Table 1). Sample = 24 subjects.

Figure 7. Functional Connectivity during gastric distention.

Statistically significant cross-correlations among time-varying fMRI signals in the 27 ROIs listed in Table 1; Sample: 24 subjects, 90 fMRI runs; t-test; statistical threshold P _c<0.05 (Bonferroni correction for 351 comparisons).