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

Abstract

Depression is associated with systemic inflammation, and endotoxin administration, which causes systemic inflammation, 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 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. FDG-PET was used to measure differences in the cerebral metabolic rate of glucose in regions of interest: insula, cingulate, and amygdala. Serum levels of tumor necrosis factor-alpha and interleukin-6 were used to gauge the systemic inflammatory response, and depressive symptoms were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) and other scales. Results Endotoxin administration was associated with an increase in MADRS score, 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.

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…Vital signs were closely monitored after LPS administration. By the start of the LPS challenge scan, there was a nonclinically significant decrease in systolic (−5 mmHg) and diastolic (−10 mmHg) blood pressure, and an increase in heart rate (+25 bpm) and temperature (+2.0°C) from baseline levels, consistent with findings from previous studies (32,36).…”

“…LPS is well known for its ability to produce sickness behaviors in preclinical (14,(38)(39)(40)(41) and clinical (33,36,42) studies, and it is thought that these symptoms result from the effect on the brain of the increases in blood serum levels of cytokines. Subjects were asked to rate sickness symptoms (fatigue, headache, muscle pain, and shivering) on a scale from 0 (least) to 4 (most) before and at various time points after LPS administration (Fig.…”

The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: A [11C]PBR28 PET study

“…This suggests that systemic inflammation may contribute to producing depressive symptoms. In support of this, a large body of literature shows that inflammatory stimuli can produce depressive-like symptoms in individuals without depression (Wright et al, 2005; Capuron et al, 2007, 2009; Eisenberger et al, 2010a, b; Hannestad et al, 2011b; Dellagioia et al, 2013) and modulate neuronal activity in regions that are implicated in depression (Capuron et al, 2007; Harrison et al, 2009; Eisenberger et al, 2010a, b; Hannestad et al, 2012b; Inagaki et al, 2012). Although the question of whether inflammation is a cause or an effect of depression has not been resolved, some evidence suggests that inflammation may contribute to specific symptoms in individuals with depressive disorders.…”

Interoceptive dysfunction: Toward an integrated framework for understanding somatic and affective disturbance in depression.

“…The causal implications of such correlations have been confirmed in studies employing LPS and vaccine injections (see Schedlowski, Engler, & Grigoleit, 2014). Immune-activating injections result in significant decrements in mood, feelings of social connectedness, and social interest—changes that correlate with the magnitude of immune response (e.g., Eisenberger, Inagaki, Marshal, & Irwin, 2010; Hannestad et al, 2012; Reichenberg et al, 2001; Wright, Strike, Brydon, & Steptoe, 2005). For example, Reichenberg et al (2001) found that LPS injection resulted in significant increase in anxiety followed by significant increase in depressed mood in healthy participants.…”