Inflammation Causes Mood Changes Through Alterations in Subgenual Cingulate Activity and Mesolimbic Connectivity

Abstract

BackgroundInflammatory cytokines are implicated in the pathophysiology of depression. In rodents, systemically administered inflammatory cytokines induce depression-like behavior. Similarly in humans, therapeutic interferon-α induces clinical depression in a third of patients. Conversely, patients with depression also show elevated pro-inflammatory cytokines.ObjectivesTo determine the neural mechanisms underlying inflammation-associated mood change and modulatory effects on circuits involved in mood homeostasis and affective processing.MethodsIn 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.ResultsTyphoid 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.ConclusionsInflammation-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.

Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study

“…Immunoactivation in mice and healthy volunteers by injection of lipopolysaccharide has been reported to increase circulating proinflammatory cytokine levels (IL-1β, IL-6) as well as producing symptoms of anxiety and reduced cognitive performance (Reichenberg et al 2001;Rossi et al 2012). A study of human volunteers suggests inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity, which is in part mediated by peripheral IL-6 (Harrison et al 2009). An immunological understanding of major mental illness could potentially lead to novel approaches to diagnosis, prevention and treatment.…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Studies using IFN-α, typhoid vaccination, and endotoxin in humans have all identified motivational circuits and symptoms of anhedonia as being primary targets of inflammatory stimuli on the brain and behavior (Brydon et al, 2008;Harrison et al, 2009aHarrison et al, , b, 2015aEisenberger et al, 2010a;Capuron et al, 2012;Dowell et al, 2015). In addition, studies in patients with depression have also indicated strong relationships between peripheral inflammatory markers (eg, CRP) and changes in reward circuitry as well as alterations in glutamate metabolism in the basal ganglia, both of which were associated with symptoms of anhedonia Felger et al, 2016).…”

The Age-by-Disease Interaction Hypothesis of Late-Life Depression

“…For example, aging leads to an exaggerated and prolonged inflammatory response in the brain, and such dysregulation of inflammatory responses leads to emotional and cognitive changes reminiscent of LLD. 35-37 Further, antidepressants have been shown to reduce inflammatory markers 38-40 and some anti-inflammatory agents appear to have antidepressant properties. 41-43 …”