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


OBJECTIVE
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.
Wellcome Trust, Centre for Neuroimaging, Institute of Cognitive Neuroscience, UCL, 17 Queen Square, London WC1N 3AR, UK. n.harrison@fil.ion.ucl.ac.uk
Neil A
NA
Harrison
Lena
L
Brydon
Cicely
C
Walker
Marcus A
MA
Gray
Andrew
A
Steptoe
Hugo D
HD
Critchley
D000328:Adult; D000339:Affect / Q000502:physiology*; D005149:Facial Expression; D006179:Gyrus Cinguli / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000503:physiopathology* / Q000523:psychology*; D015850:Interleukin-6 / Q000097:blood; D008032:Limbic System / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology*; D014436:Typhoid-Paratyphoid Vaccines
D015850:Interleukin-6; D014436:Typhoid-Paratyphoid Vaccines