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

Neil A Harrison, Lena Brydon, Cicely Walker, Marcus A Gray, Andrew Steptoe, Hugo D Critchley, Neil A Harrison, Lena Brydon, Cicely Walker, Marcus A Gray, Andrew Steptoe, Hugo D Critchley

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.

Figures

Figure 1
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
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
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.

References

    1. Raison C.L., Capuron L., Miller A.H. Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.
    1. Capuron L., Lamarque D., Dantzer R., Goodall G. Attentional and mnemonic deficits associated with infectious disease in humans. Psychol Med. 1999;29:291–297.
    1. Maier S.F., Watkins L.R. Cytokines for psychologists: Implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev. 1998;105:83–107.
    1. Reichenberg A., Yirmiya R., Schuld A., Kraus T., Haack M., Morag A. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445–452.
    1. Kent S., Bluthe R.M., Dantzer R., Hardwick A.J., Kelley K.W., Rothwell N.J. Different receptor mechanisms mediate the pyrogenic and behavioral-effects of interleukin-1. Proc Natl Acad Sci U S A. 1992;89:9117–9120.
    1. Merali Z., Brennan K., Brau P., Anisman H. Dissociating anorexia and anhedonia elicited by interleukin-1beta: Antidepressant and gender effects on responding for “free chow” and “earned” sucrose intake. Psychopharmacology. 2003;165:413–418.
    1. Larson S.J., Romanoff R.L., Dunn A.J., Glowa J.R. Effects of interleukin-1beta on food-maintained behavior in the mouse. Brain Behav Immun. 2002;16:398–410.
    1. Stone E.A., Lehmann M.L., Lin Y., Quartermain D. Depressive behavior in mice due to immune stimulation is accompanied by reduced neural activity in brain regions involved in positively motivated behavior. Biol Psychiatry. 2006;60:803–811.
    1. Dantzer R., Bluthe R.M., Castanon N., Kelley K.W., Konsman J.P., Laye S. Cytokines, sickness behavior and depression. In: Ader R., editor. Psychoneuroimmunology. 4th edition. Elsevier; Amsterdam: 2007. pp. 281–318.
    1. Strike P.C., Wardle J., Steptoe A. Mild acute inflammatory stimulation induces transient negative mood. J Psychosom Res. 2004;57:189–194.
    1. Wright C.E., Strike P.C., Brydon L., Steptoe A. Acute inflammation and negative mood: Mediation by cytokine activation. Brain Behav Immun. 2005;19:345–350.
    1. Capuron L., Gumnick J.F., Musselman D.L., Lawson D.H., Reemsnyder A., Nemeroff C.B. Neurobehavioral effects of interferon-alpha in cancer patients: Phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26:643–652.
    1. Zorrilla E.P., Luborsky L., Mckay J.R., Rosenthal R., Houldin A., Tax A. The relationship of depression and stressors to immunological assays: A meta-analytic review. Brain Behav Immun. 2001;15:199–226.
    1. Miller G.E., Stetler C.A., Carney R.M., Freedland K.E., Banks W.A. Clinical depression and inflammatory risk markers for CHD. Psychosom Med. 2002;64:101.
    1. Musselman D.L., Lawson D.H., Gumnick J.F., Manatunga A.K., Penna S., Goodkin R.S. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961–966.
    1. Harrison N.A., Brydon L., Walker C., Gray M., Steptoe A., Dolan R.J. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry. 2009;66:415–422.
    1. Wan W.H., Wetmore L., Sorensen C.M., Greenberg A.H., Nance D.M. Neural and biochemical mediators of endotoxin and stress-induced c-Fos expression in the rat-brain. Brain Res Bull. 1994;34:7–14.
    1. Goehler L.E., Relton J.K., Dripps D., Kiechle R., Tartaglia N., Maier S.F. Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: A possible mechanism for immune-to-brain communication. Brain Res Bull. 1997;43:357–364.
    1. Brydon L., Harrison N.A., Walker C., Steptoe A., Critchley H.D. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry. 2008;63:1022–1029.
    1. Fu C.H.Y., Williams S.C.R., Cleare A.J., Brammer M.J., Walsh N.D., Kim J. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: A prospective, event-related functional magnetic resonance imaging study. Arch Gen Psychiatry. 2004;61:877–889.
    1. McNair D.M., Lorr N., Droppleman L.F. Education and Industrial Testing Service; San Diego: 1981. Manual for the Profile of Mood States.
    1. Hingorani A.D., Cross J., Kharbanda R.K., Mullen M.J., Bhagat K., Taylor M. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation. 2000;102:994–999.
    1. Lundqvist D., Flykt A., Öhmann A. Department of Clinical Neuroscience, Psychology Section, Karolinska Institutet [CD-ROM, ISBN 91-630-7164-9]; Stockholm: 1998. The Karolinska Directed Emotional Faces (KDEF)
    1. Vuilleumier P., Armony J.L., Driver J., Dolan R.J. Distinct spatial frequency sensitivities for processing faces and emotional expressions. Nat Neurosci. 2003;6:624–631.
    1. Deichmann R., Gottfried J.A., Hutton C., Turner R. Optimized EPI for fMRI studies of the orbitofrontal cortex. Neuroimage. 2003;19:430–441.
    1. Brett M., Anton J.-C., Valabregue R., Poline J.-B. Region of interest analysis using an SPM toolbox. Neuroimage. 2002;16 [CD-ROM] Presented at: 8th International Conference on Functional Mapping of the Human Brain, Sendai, Japan, June 2–6.
    1. Mayberg H.S., Lozano A.M., Voon V., McNeely H.E., Seminowicz D., Hamani C. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651–660.
    1. Keedwell P.A., Andrew C., Williams S.C.R., Brammer M.J., Zelaya F., Phillips M.L. The neural correlates of depression. Biol Psychiatry. 2003;53:171S.
    1. Kanwisher N., McDermott J., Chun M.M. The fusiform face area: A module in human extrastriate cortex specialized for face perception. J Neurosci. 1997;17:4302–4311.
    1. Vuilleumier P., Armony J.L., Driver J., Dolan R.J. Effects of attention and emotion on face processing in the human brain: An event-related fMRI study. Neuron. 2001;30:829–841.
    1. Winston J.S., O'Doherty J., Dolan R.J. Common and distinct neural responses during direct and incidental processing of multiple facial emotions. Neuroimage. 2003;20:84–97.
    1. Kendler K.S., Neale M.C., Kessler R.C., Heath A.C., Eaves L.J. A longitudinal twin study of personality and major depression in women. Arch Gen Psychiatry. 1993;50:853–862.
    1. Capuron L., Ravaud A. Prediction of the depressive effects of interferon alfa therapy by the patient's initial affective state. N Engl J Med. 1999;340:1370.
    1. Anand A., Li Y., Wang Y., Wu J.W., Gao S.J., Bukhari L. Activity and connectivity of brain mood regulating circuit in depression: A functional magnetic resonance study. Biol Psychiatry. 2005;57:1079–1088.
    1. Mayberg H.S. Modulating dysfunctional limbic-cortical circuits in depression: Towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull. 2003;65:193–207.
    1. Seminowicz D.A., Mayberg H.S., McIntosh A.R., Goldapple K., Kennedy S., Segal Z. Limbic-frontal circuitry in major depression: A path modeling metanalysis. Neuroimage. 2004;22:409–418.
    1. Mazaheri A., McIntosh A.R., Mayberg H. Functional connectivity of the rostral cingulate predicts treatment response in unipolar depression. Biol Psychiatry. 2002;51:33S.
    1. Mayberg H.S., Liotti M., Brannan S.K., McGinnis S., Mahurin R.K., Jerabek P.A. Reciprocal limbic-cortical function and negative mood: Converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156:675–682.
    1. Mayberg H.S., Brannan S.K., Tekell J.L., Silva J.A., Mahurin R.K., McGinnis S. Regional metabolic effects of fluoxetine in major depression: Serial changes and relationship to clinical response. Biol Psychiatry. 2000;48:830–843.
    1. Konarski J., Kennedy S., McIntyre R., Mayberg H., Segal Z. Neurobiological correlates of remission. Int J Neuropsychopharmacology. 2006;9:S240.
    1. Sheline Y.I., Barch D.M., Donnelly J.M., Ollinger J.M., Snyder A.Z., Mintun M.A. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: An fMRI study. Biol Psychiatry. 2001;50:651–658.
    1. Thomas K.M., Drevets W.C., Dahl R.E., Ryan N.D., Birmaher B., Eccard C.H. Amygdala response to fearful faces in anxious and depressed children. Arch Gen Psychiatry. 2001;58:1057–1063.
    1. Rosenkranz M.A., Busse W.W., Johnstone T., Swenson C.A., Crisafi G.M., Jackson M.M. Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation. Proc Natl Acad Sci U S A. 2005;102:13319–13324.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する