Glucose Metabolism in the Insula and Cingulate Is Affected by Systemic Inflammation in Humans

Depression is associated with systemic inflammation, and the systemic inflammation caused by endotoxin administration elicits mild depressive symptoms such as fatigue and reduced interest. The neural correlates of depressive symptoms that result from systemic inflammation are poorly defined. The aim of this study was to use F-18-FDG PET to identify brain regions involved in the response to endotoxin administration in humans. Methods: Nine healthy subjects received double-blind endotoxin (0.8 ng/kg) and placebo on different days. F-18-FDG PET was used to measure differences in the cerebral metabolic rate of glucose in the following regions of interest: insula, cingulate, and amygdala. Serum levels of tumor necrosis factor-a and interleukin-6 were used to gauge the systemic inflammatory response, and depressive symptoms were measured with the Montgomery-Asberg Depression Rating Scale and other scales. Results: Endotoxin administration was associated with an increase in Montgomery-Asberg Depression Rating Scale, increased fatigue, reduced social interest, increased levels of inflammatory cytokines, higher normalized glucose metabolism (NGM) in the insula, and, at a trend level, lower NGM in the cingulate. Secondary analyses of insula and cingulate subregions indicated that these changes were driven by the right anterior insula and the right anterior cingulate. There was a negative correlation between peak cytokine levels and change in social interest and between peak cytokine levels and change in insula NGM. There was a positive correlation between the change in NGM in the insula and change in social interest. Conclusion: Systemic inflammation in humans causes an increase in depressive symptoms and concurrent changes in glucose metabolism in the insula and cingulate-brain regions that are involved in interoception, positive emotionality, and motivation.