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

By Neil A. Harrison, L. Brydon, Cicely Walker, Marcus A. Gray, Andrew Steptoe, Hugo D. Critchley. Biological Psychiatry, 2009

736 citations recorded by the source corpus.

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-α 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.

Subfields: Behavioral Neuroscience, Biological Psychiatry, Experimental and Cognitive Psychology

View Paper: https://www.semanticscholar.org/paper/b99b05da42e9048009e7a9ae73e5d5ee77682d06

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Citations in the corpus

Early-Life Adversity and Physical and Emotional Health across the Lifespan: A Neuro-Immune Network Hypothesis (2015, background): “Compared with placebo, typhoidtreated subjects showed disrupted functional connections between the subgenual ACC and the ventral striatum, among other subcortical regions involved in reward processing (84).”
Conjoint activity of anterior insular and anterior cingulate cortex: awareness and response (2010, background): “…and discomfort induced by gastro-intestinal stimulation (see above) have some relevance here, but the experience of feeling unwell has been assessed more directly by a recent study examining neural activity associated with an inflammatory response induced by typhoid vaccine (Harrison et al. 2009b).”
The Bidirectional Relationship of Depression and Inflammation: Double Trouble (2020, background): “, endotoxin [LPS] or Salmonella typhi administrations) are known to activate microglia and induce depressive symptoms; the severity of the symptoms directly correlates with high blood levels of proinflammatory cytokines (Grigoleit et al., 2011; Harrison et al., 2009; Reichenberg et al., 2001).”
Cytokine Targets in the Brain: Impact on Neurotransmitters and Neurocircuits (2013, background): “[30–34] The third body of data that supports the association of inflammation with symptoms of depression and anxiety are studies that have used drugs that inhibit inflammatory cytokines or their signaling pathways to reduce depression and anxiety.”
Reciprocal regulation of the neural and innate immune systems (2011, background): “The findings have shown altered connectivity between the subgenual anterior cingulate cortex, amygdala and medial prefrontal corte”
Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications (2013, background): “…comes from neuoroimaging studies in humans examining basal ganglia activity after administration of IFN-alpha or immune activating stimuli (e.g. LPS or typhoid vaccination) (Capuron et al., 2007, Brydon et al., 2008, Harrison et al., 2009b, Eisenberger et al., 2010, Capuron et al., 2012).”
Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior (2012, methodology): “Aside from IFN-a, increased activation of the dACC has been found using fMRI after a high-demand color word Stroop task in patients administered typhoid vaccination (Harrison et al, 2009a, b).”
Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017, background): “Importantly, these increases in cytokine activity and amygdala responsivity to stress exposure are also associated with greater social disconnection and depressed mood (Muscatell et al, 2015), as well as cognitive disturbance and increased fatigue (Harrison et al, 2009b).”
Depression as a microglial disease. (2015, background): “, endotoxin (lipopolysaccharide, LPS) or Salmonella typhi] induces depressive symptoms, whose severity is highly correlated with elevated blood levels of inflammatory cytokines [14–16].”
Depressive Rumination, the Default-Mode Network, and the Dark Matter of Clinical Neuroscience (2015, background): “…report elevated sgPFC activity associated with a state of depression (42–44) or with response to negative affective challenge in MDD (46) or, in non-depressed persons, with sad mood induced either through elaboration of sad autobiographical scripts (43) or through inflammation challenge (53).”