Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity

Abstract

Background: Inflammatory cytokines are implicated in the pathophysiology of depression. In rodents, systemically administered inflammatory cytokines induce depression-like behavior. Similarly in humans, therapeutic interferon-alpha induces clinical depression in a third of patients. Conversely, patients with depression also show elevated pro-inflammatory cytokines.

Objectives: To determine the neural mechanisms underlying inflammation-associated mood change and modulatory effects on circuits involved in mood homeostasis and affective processing.

Methods: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Mood questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed an implicit emotional face perception task during functional magnetic resonance imaging. Analyses focused on neurobiological correlates of inflammation-associated mood change and affective processing within regions responsive to emotional expressions and implicated in the etiology of depression.

Results: Typhoid but not placebo injection produced an inflammatory response indexed by increased circulating interleukin-6 and significant mood reduction at 3 hours. Inflammation-associated mood deterioration correlated with enhanced activity within subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotional face processing. Furthermore, inflammation-associated mood change reduced connectivity of sACC to amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6.

Conclusions: Inflammation-associated mood deterioration is reflected in changes in sACC activity and functional connectivity during evoked responses to emotional stimuli. Peripheral cytokines modulate this mood-dependent sACC connectivity, suggesting a common pathophysiological basis for major depressive disorder and sickness-associated mood change and depression.

Figure 1

Study timeline. Participants completed mood rating questionnaires (Profile of Mood States [POMS]) and underwent venesection, then randomly received Salmonella typhi capsular polysaccharide vaccination (Typhim Vi, Aventis Pasteur MSD, Berkshire, United Kingdom) or normal saline placebo injection on two separate occasions 1 week apart. Two hours after injection, participants completed a flashing checkerboard control task, then an implicit facial emotion recognition task during functional magnetic resonance imaging. The POMS and venesection were repeated at 3 hours. Facial expressions reproduced with permission from the Section of Psychology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (23).

Figure 2

Subgenual cingulate (subgenual anterior cingulate cortex [sACC], Cg25) activity predicts inflammation-associated total mood change. (A) Region of subgenual cingulate (Cg25), which shows the strongest prediction of inflammation-associated deterioration in total mood. (B) Correlation of activity in an 8-mm diameter region of interest centered on the peak subgenual cingulate voxel (−2, 22–28) (ordinate) with inflammation-associated total mood change (abscissa). (C) Area of placement of deep brain stimulation electrodes for the treatment of primary depression (27) showing relative position with respect to activation shown in A. Reprinted from Neuron, volume 45, Mayberg et al., “Deep brain stimulation for treatment-resistant depression,” 651–660, copyright 2005, with permission from Elsevier (27).

Figure 3

Psychophysiological interaction between inflammation-associated total mood change and subgenual cingulate (Cg25) activity. (A) Inflammation-associated change in total mood correlates with reduction in connectivity between subgenual cingulate and bilateral nucleus accumbens. (B) Region of anterior rostral medial prefrontal cortex showing reduced connectivity to subgenual cingulate with greater inflammation-induced mood change. (C) Inflammation-associated change in total mood correlates with reduced subgenual cingulate connectivity to superior temporal sulcus.