Hypothalamic effective connectivity at rest is associated with body weight and energy homeostasis

Hunger and satiety drive eating behaviours via changes in brain function. The hypothalamus is a central component of the brain networks that regulate food intake. Animal research parsed the roles of the lateral hypothalamus (LH) and medial hypothalamus (MH) in hunger and satiety, respectively. Here, we examined how hunger and satiety change information flow between human LH and MH brain networks, and how these interactions are influenced by body mass index (BMI). Forty participants (16 overweight/obese) underwent two resting-state functional MRI scans while being fasted and sated. The excitatory/inhibitory influence of information flow between the MH and LH was modelled using spectral dynamic causal modelling. Our results revealed two core networks interacting across homeostatic state and weight: subcortical bidirectional connections between the LH, MH and the substantia nigra pars compacta (prSN), and cortical top-down inhibition from fronto-parietal and temporal areas. During fasting, we found higher inhibition between the LH and prSN, whereas the prSN received greater top-down inhibition from across the cortex. Individuals with higher BMI showed that these network dynamics occur irrespective of homeostatic state. Our findings reveal fasting affects brain dynamics over a distributed hypothalamic-midbrain-cortical network. This network is less sensitive to state-related fluctuations among people with obesity. Author Summary The hypothalamus is a central component of the brain networks regulating food intake. Animal research subdivided the hypothalamus anatomically and functionally into lateral hypothalamus (LH) and medial hypothalamus (MH). This is the first study showing how the LH and MH causally interact with other neural regions and how their dynamics change with weight and homeostasis in humans. Adopting state-of-the-art spectral dynamic causal modelling of resting-state fMRI data, we provide new insights into how homeostasis affect hypothalamic circuit dynamics, which involve a distributed network of midbrain and cortical areas with a key role of the substantia nigra. We identified unique aspects of network organisation associated with obesity involving reciprocal connections between the LH and MH, and input from the substantia nigra to the MH.