Neural network modelling reveals changes in directional connectivity between cortical and hypothalamic regions in obesity

Obesity has been ascribed to corticostriatal regions taking control over homeostatic areas. To test this assumption, we applied an effective connectivity approach to reveal the direction of information flow between brain regions and the valence of connections (excitatory versus inhibitory) as a function of adiposity and homeostatic state. Forty-one participants (21 overweight/obese) underwent two resting-state fMRI scans: after overnight fasting (hunger) and following a standardised meal (satiety). We used spectral dynamic causal modelling to unravel hunger and adiposity related changes in directed connectivity between cortical, insular, striatal and hypothalamic regions. During hunger, as compared to satiety, we found increased excitation of the ventromedial prefrontal cortex over the ventral striatum and hypothalamus, suggesting enhanced top-down modulation compensating energy depletion. Adiposity was associated with increased excitation of the anterior insula over the hypothalamus across the hunger and satiety conditions. The interaction of hunger and adiposity yielded decreased intra-cortical excitation from the dorsolateral to the ventromedial prefrontal cortex. Our findings suggest that obesity is associated with persistent top-down excitation of the hypothalamus, regardless of homeostatic state, and hunger-related reductions of dorsolateral to ventromedial prefrontal inputs. These findings are compatible with eating without hunger and reduced self-regulation views of obesity. Significance StatementObesity is a leading contributor to morbidity and mortality. Neurobiological theories propose that, in obese people, corticostriatal regions take over homeostatic areas. Neuroimaging-based functional connectivity is well-poised to unravel such abnormalities by examining between-regions communication, but existing studies have only measured signal covariance, not direction and valence of connectivity. We applied computational modelling to reveal the direction of information flow between brain regions and excitatory/inhibitory valence of connections in obese versus healthy-weight participants. Obesity associated with heightened top-down excitation from the insula to hypothalamus, and reduced excitation within prefrontal regions. Findings have two advantages relative to current knowledge: demonstrate theory-based directional abnormalities, i.e. cortical regions taking over homeostatic areas; and inform brain stimulation therapies targeting cortical input to lower-level regions.