The Central Inflammatory Network: A Hypothalamic fMRI Study of Experimental Endotoxemia in Humans

INTRODUCTION: Inflammation is a mechanism of the immune system that is part of the reaction to pathogens or injury. The central nervous system closely regulates inflammation via neuroendocrine or direct neuroimmune mechanisms, but our current knowledge of the underlying circuitry is limited. Therefore, we aimed to identify hypothalamic centres involved in sensing or modulating inflammation and to study their association with known large-scale brain networks. METHODS: Using high-resolution functional magnetic resonance imaging (fMRI), we recorded brain activity in healthy male subjects undergoing experimental inflammation from intravenous endotoxin. Four fMRI runs covered key phases of the developing inflammation: pre-inflammatory baseline, onset of endotoxemia, onset of pro-inflammatory cytokinemia, and peak of pro-inflammatory cytokinemia. Using masked independent component analysis, we identified functionally homogeneous subregions of the hypothalamus, which were further tested for changes in functional connectivity during inflammation and for temporal correlation with tumour necrosis factor and adrenocorticotropic hormone serum levels. We then studied the connection of these inflammation-associated hypothalamic subregions with known large-scale brain networks. RESULTS: Our results show that there are at least 6 hypothalamic subregions associated with inflammation in humans including the paraventricular nucleus, supraoptic nucleus, dorsomedial hypothalamus, bed nucleus of the stria terminalis, lateral hypothalamic area, and supramammillary nucleus. They are functionally embedded in at least 3 different large-scale brain networks, namely a medial frontoparietal network, an occipital-pericentral network, and a midcingulo-insular network. CONCLUSION: Measuring how the hypothalamus detects or modulates systemic inflammation is a first step to understand central nervous immunomodulation.