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Interoception and Inflammation in Psychiatric Disorders

  • Jonathan Savitz
    Affiliations
    Laureate Institute for Brain Research, the University of Tulsa, Tulsa, Oklahoma

    Oxley College of Health Sciences, the University of Tulsa, Tulsa, Oklahoma
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  • Neil A. Harrison
    Correspondence
    Address correspondence to Neil A. Harrison, M.B.B.S., Ph.D., Clinical Imaging Sciences Centre, Department of Neuroscience, Brighton & Sussex Medical School, University of Sussex, Falmer, BN1 9RR, United Kingdom.
    Affiliations
    Clinical Imaging Sciences Centre, Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom

    Sackler Centre for Consciousness Science, University of Sussex, Brighton, United Kingdom

    Sussex Partnership NHS Foundation Trust, Brighton, United Kingdom
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Published:January 09, 2018DOI:https://doi.org/10.1016/j.bpsc.2017.12.011

      Abstract

      Despite a historical focus on neurally mediated interoceptive signaling mechanisms, humoral (and even cellular) signals also play an important role in communicating bodily physiological state to the brain. These signaling pathways can perturb neuronal structure, chemistry, and function, leading to discrete changes in behavior. They are also increasingly implicated in the pathophysiology of psychiatric disorders. The importance of these humoral signaling pathways is perhaps most powerfully illustrated in the context of infection and inflammation. Here we provide an overview of how interaction of immune activation of neural and humoral interoceptive mechanisms mediates discrete changes in brain and behavior and highlight how activation of these pathways at specific points in neural development may predispose to psychiatric disorder. As our mechanistic understanding of these interoceptive pathways continues to emerge, it is revealing novel therapeutic targets, potentially heralding an exciting new era of immunotherapies in psychiatry.

      Keywords

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      References

        • Harrison N.A.
        Brain structures implicated in inflammation-associated depression.
        Curr Top Behav Neurosci. 2017; 31: 221-248
        • Kelley K.W.
        • Bluthe R.M.
        • Dantzer R.
        • Zhou J.H.
        • Shen W.H.
        • Johnson R.W.
        • et al.
        Cytokine-induced sickness behavior.
        Brain Behav Immun. 2003; 17: S112-S118
        • Yirmiya R.
        • Goshen I.
        Immune modulation of learning, memory, neural plasticity and neurogenesis.
        Brain Behav Immun. 2011; 25: 181-213
        • Tracey K.J.
        Reflex control of immunity.
        Nat Rev Immunol. 2009; 9: 418-428
        • Irwin M.R.
        • Cole S.W.
        Reciprocal regulation of the neural and innate immune systems.
        Nat Rev Immunol. 2011; 11: 625-632
        • Pacheco-Lopez G.
        • Bermudez-Rattoni F.
        Brain-immune interactions and the neural basis of disease-avoidant ingestive behaviour.
        Philos Trans R Soc Lond B Biol Sci. 2011; 366: 3389-3405
        • Wohleb E.S.
        • McKim D.B.
        • Sheridan J.F.
        • Godbout J.P.
        Monocyte trafficking to the brain with stress and inflammation: A novel axis of immune-to-brain communication that influences mood and behavior.
        Front Neurosci. 2014; 8: 447
        • Hart B.L.
        Biological basis of the behavior of sick animals.
        Neurosci Biobehav Rev. 1988; 12: 123-137
        • Miller A.H.
        • Maletic V.
        • Raison C.L.
        Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression.
        Biol Psychiatry. 2009; 65: 732-741
        • Bilbo S.D.
        • Schwarz J.M.
        Early-life programming of later-life brain and behavior: A critical role for the immune system.
        Front Behav Neurosci. 2009; 3: 14
        • Perry V.H.
        • Holmes C.
        Microglial priming in neurodegenerative disease.
        Nat Rev Neurol. 2014; 10: 217-224
        • Wohleb E.S.
        • Powell N.D.
        • Godbout J.P.
        • Sheridan J.F.
        Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior.
        J Neurosci. 2013; 33: 13820-13833
        • Netea M.G.
        • Latz E.
        • Mills K.H.
        • O'Neill L.A.
        Innate immune memory: A paradigm shift in understanding host defense.
        Nat Immunol. 2015; 16: 675-679
        • Wan W.
        • 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
        • Goehler L.E.
        • Relton J.K.
        • Dripps D.
        • Kiechle R.
        • Tartaglia N.
        • Maier S.F.
        • et al.
        Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: A possible mechanism for immune-to-brain communication.
        Brain Res Bull. 1997; 43: 357-364
        • Ek M.
        • Kurosawa M.
        • Lundeberg T.
        • Ericsson A.
        Activation of vagal afferents after intravenous injection of interleukin-1beta: Role of endogenous prostaglandins.
        J Neurosci. 1998; 18: 9471-9479
        • Goehler L.E.
        • Gaykema R.P.
        • Hansen M.K.
        • Anderson K.
        • Maier S.F.
        • Watkins L.R.
        Vagal immune-to-brain communication: A visceral chemosensory pathway.
        Auton Neurosci. 2000; 85: 49-59
        • Hannestad J.
        • Subramanyam K.
        • Dellagioia N.
        • Planeta-Wilson B.
        • Weinzimmer D.
        • Pittman B.
        • et al.
        Glucose metabolism in the insula and cingulate is affected by systemic inflammation in humans.
        J Nucl Med. 2012; 53: 601-607
        • Harrison N.A.
        • Brydon L.
        • Walker C.
        • Gray M.A.
        • Steptoe A.
        • Dolan R.J.
        • et al.
        Neural origins of human sickness in interoceptive responses to inflammation.
        Biol Psychiatry. 2009; 66: 415-422
        • Harrison N.A.
        • Cooper E.
        • Dowell N.G.
        • Keramida G.
        • Voon V.
        • Critchley H.D.
        • et al.
        Quantitative magnetization transfer imaging as a biomarker for effects of systemic inflammation on the brain.
        Biol Psychiatry. 2015; 78: 49-57
        • Critchley H.D.
        • Harrison N.A.
        Visceral influences on brain and behavior.
        Neuron. 2013; 77: 624-638
        • Barrett L.F.
        • Simmons W.K.
        Interoceptive predictions in the brain.
        Nat Rev Neurosci. 2015; 16: 419-429
        • Seth A.K.
        • Suzuki K.
        • Critchley H.D.
        An interoceptive predictive coding model of conscious presence.
        Front Psychol. 2011; 2: 395
        • Stephan K.E.
        • Manjaly Z.M.
        • Mathys C.D.
        • Weber L.A.
        • Paliwal S.
        • Gard T.
        • et al.
        Allostatic self-efficacy: A metacognitive theory of dyshomeostasis-induced fatigue and depression.
        Front Hum Neurosci. 2016; 10: 550
        • Dantzer R.
        • O'Connor J.C.
        • Freund G.G.
        • Johnson R.W.
        • Kelley K.W.
        From inflammation to sickness and depression: When the immune system subjugates the brain.
        Nat Rev Neurosci. 2008; 9: 46-56
        • Gross P.M.
        Morphology and physiology of capillary systems in subregions of the subfornical organ and area postrema.
        Can J Physiol Pharmacol. 1991; 69: 1010-1025
        • Banks W.A.
        From blood-brain barrier to blood-brain interface: New opportunities for CNS drug delivery.
        Nat Rev Drug Discov. 2016; 15: 275-292
        • Evans S.S.
        • Repasky E.A.
        • Fisher D.T.
        Fever and the thermal regulation of immunity: The immune system feels the heat.
        Nat Rev Immunol. 2015; 15: 335-349
        • Schulz C.
        • Gomez Perdiguero E.
        • Chorro L.
        • Szabo-Rogers H.
        • Cagnard N.
        • Kierdorf K.
        • et al.
        A lineage of myeloid cells independent of Myb and hematopoietic stem cells.
        Science. 2012; 336: 86-90
        • Nimmerjahn A.
        • Kirchhoff F.
        • Helmchen F.
        Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.
        Science. 2005; 308: 1314-1318
        • Schafer D.P.
        • Lehrman E.K.
        • Kautzman A.G.
        • Koyama R.
        • Mardinly A.R.
        • Yamasaki R.
        • et al.
        Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.
        Neuron. 2012; 74: 691-705
        • Prinz M.
        • Priller J.
        Microglia and brain macrophages in the molecular age: From origin to neuropsychiatric disease.
        Nat Rev Neurosci. 2014; 15: 300-312
        • Weber M.D.
        • Godbout J.P.
        • Sheridan J.F.
        Repeated social defeat, neuroinflammation, and behavior: Monocytes carry the signal.
        Neuropsychopharmacology. 2017; 42: 46-61
        • Rivest S.
        Regulation of innate immune responses in the brain.
        Nat Rev Immunol. 2009; 9: 429-439
        • Saper C.B.
        • Romanovsky A.A.
        • Scammell T.E.
        Neural circuitry engaged by prostaglandins during the sickness syndrome.
        Nat Neurosci. 2012; 15: 1088-1095
        • Laflamme N.
        • Rivest S.
        Toll-like receptor 4: The missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components.
        FASEB J. 2001; 15: 155-163
        • Sandiego C.M.
        • Gallezot J.D.
        • Pittman B.
        • Nabulsi N.
        • Lim K.
        • Lin S.F.
        • et al.
        Imaging robust microglial activation after lipopolysaccharide administration in humans with PET.
        Proc Natl Acad Sci U S A. 2015; 112: 12468-12473
        • Baumeister D.
        • Akhtar R.
        • Ciufolini S.
        • Pariante C.M.
        • Mondelli V.
        Childhood trauma and adulthood inflammation: A meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-alpha.
        Mol Psychiatry. 2016; 21: 642-649
        • Felger J.C.
        • Li Z.
        • Haroon E.
        • Woolwine B.J.
        • Jung M.Y.
        • Hu X.
        • et al.
        Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression.
        Mol Psychiatry. 2016; 21: 1358-1365
        • Brevet M.
        • Kojima H.
        • Asakawa A.
        • Atsuchi K.
        • Ushikai M.
        • Ataka K.
        • et al.
        Chronic foot-shock stress potentiates the influx of bone marrow-derived microglia into hippocampus.
        J Neurosci Res. 2010; 88: 1890-1897
        • Haapakoski R.
        • Mathieu J.
        • Ebmeier K.P.
        • Alenius H.
        • Kivimaki M.
        Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder.
        Brain Behav Immun. 2015; 49: 206-215
        • Mostafavi S.
        • Battle A.
        • Zhu X.
        • Potash J.B.
        • Weissman M.M.
        • Shi J.
        • et al.
        Type I interferon signaling genes in recurrent major depression: Increased expression detected by whole-blood RNA sequencing.
        Mol Psychiatry. 2014; 19: 1267-1274
        • Jansen R.
        • Penninx B.W.
        • Madar V.
        • Xia K.
        • Milaneschi Y.
        • Hottenga J.J.
        • et al.
        Gene expression in major depressive disorder.
        Mol Psychiatry. 2016; 21: 339-347
        • Savitz J.
        • Frank M.B.
        • Victor T.
        • Bebak M.
        • Marino J.H.
        • Bellgowan P.S.
        • et al.
        Inflammation and neurological disease-related genes are differentially expressed in depressed patients with mood disorders and correlate with morphometric and functional imaging abnormalities.
        Brain Behav Immun. 2013; 31: 161-171
        • Setiawan E.
        • Wilson A.A.
        • Mizrahi R.
        • Rusjan P.M.
        • Miler L.
        • Rajkowska G.
        • et al.
        Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.
        JAMA Psychiatry. 2015; 72: 268-275
        • Raison C.L.
        • Borisov A.S.
        • Broadwell S.D.
        • Capuron L.
        • Woolwine B.J.
        • Jacobson I.M.
        • et al.
        Depression during pegylated interferon-alpha plus ribavirin therapy: Prevalence and prediction.
        J Clin Psychiatry. 2005; 66: 41-48
        • Krishnadas R.
        • Cavanagh J.
        Depression: an inflammatory illness?.
        J Neurol Neurosurg Psychiatry. 2012; 83: 495-502
        • Dowell N.G.
        • Cooper E.A.
        • Tibble J.
        • Voon V.
        • Critchley H.D.
        • Cercignani M.
        • et al.
        Acute changes in striatal microstructure predict the development of interferon-alpha induced fatigue.
        Biol Psychiatry. 2016; 79: 320-328
        • Raison C.L.
        • Borisov A.S.
        • Majer M.
        • Drake D.F.
        • Pagnoni G.
        • Woolwine B.J.
        • et al.
        Activation of central nervous system inflammatory pathways by interferon-alpha: Relationship to monoamines and depression.
        Biol Psychiatry. 2009; 65: 296-303
        • Wang J.
        • Campbell I.L.
        Innate STAT1-dependent genomic response of neurons to the antiviral cytokine alpha interferon.
        J Virol. 2005; 79: 8295-8302
        • Wang J.
        • Campbell I.L.
        • Zhang H.
        Systemic interferon-alpha regulates interferon-stimulated genes in the central nervous system.
        Mol Psychiatry. 2008; 13: 293-301
        • Lebon P.
        • Boutin B.
        • Dulac O.
        • Ponsot G.
        • Arthuis M.
        Interferon gamma in acute and subacute encephalitis.
        Br Med J (Clin Res Ed). 1988; 296: 9-11
        • Capuron L.
        • Pagnoni G.
        • Drake D.F.
        • Woolwine B.J.
        • Spivey J.R.
        • Crowe R.J.
        • et al.
        Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration.
        Arch Gen Psychiatry. 2012; 69: 1044-1053
        • Haroon E.
        • Woolwine B.J.
        • Chen X.
        • Pace T.W.
        • Parekh S.
        • Spivey J.R.
        • et al.
        IFN-alpha-induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy.
        Neuropsychopharmacology. 2014; 39: 1777-1785
        • Dowell N.G.
        • Bouyagoub S.
        • Tibble J.
        • Voon V.
        • Cercignani M.
        • Harrison N.A.
        Interferon-alpha induced changes in NODDI predispose to the development of fatigue.
        Neuroscience. 2017; ([published online ahead of print Dec 29])
        • Raison C.L.
        • Dantzer R.
        • Kelley K.W.
        • Lawson M.A.
        • Woolwine B.J.
        • Vogt G.
        • et al.
        CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: Relationship to CNS immune responses and depression.
        Mol Psychiatry. 2010; 15: 393-403
        • Saito K.
        • Markey S.P.
        • Heyes M.P.
        Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse.
        Neuroscience. 1992; 51: 25-39
        • Meier T.B.
        • Drevets W.C.
        • Wurfel B.E.
        • Ford B.N.
        • Morris H.M.
        • Victor T.A.
        • et al.
        Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder.
        Brain Behav Immun. 2016; 53: 39-48
        • Savitz J.
        • Drevets W.C.
        • Smith C.M.
        • Victor T.A.
        • Wurfel B.E.
        • Bellgowan P.S.
        • et al.
        Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder.
        Neuropsychopharmacology. 2015; 40: 463-471
        • Young K.D.
        • Drevets W.C.
        • Dantzer R.
        • Teague T.K.
        • Bodurka J.
        • Savitz J.
        Kynurenine pathway metabolites are associated with hippocampal activity during autobiographical memory recall in patients with depression.
        Brain Behav Immun. 2016; 56: 335-342
        • Wurfel B.E.
        • Drevets W.C.
        • Bliss S.A.
        • McMillin J.R.
        • Suzuki H.
        • Ford B.N.
        • et al.
        Serum kynurenic acid is reduced in affective psychosis.
        Transl Psychiatry. 2017; 7: e1115
        • Goldsmith D.R.
        • Rapaport M.H.
        • Miller B.J.
        A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder and depression.
        Mol Psychiatry. 2016; 21: 1696-1709
        • Torrey E.F.
        • Bartko J.J.
        • Lun Z.R.
        • Yolken R.H.
        Antibodies to Toxoplasma gondii in patients with schizophrenia: A meta-analysis.
        Schizophr Bull. 2007; 33: 729-736
        • Hornig M.
        • Bresnahan M.A.
        • Che X.
        • Schultz A.F.
        • Ukaigwe J.E.
        • Eddy M.L.
        • et al.
        Prenatal fever and autism risk.
        Mol Psychiatry. 2018; 23: 759-766
        • Estes M.L.
        • McAllister A.K.
        Maternal immune activation: Implications for neuropsychiatric disorders.
        Science. 2016; 353: 772-777
        • Paolicelli R.C.
        • Bolasco G.
        • Pagani F.
        • Maggi L.
        • Scianni M.
        • Panzanelli P.
        • et al.
        Synaptic pruning by microglia is necessary for normal brain development.
        Science. 2011; 333: 1456-1458
        • Richetto J.
        • Chesters R.
        • Cattaneo A.
        • Labouesse M.A.
        • Gutierrez A.M.C.
        • Wood T.C.
        • et al.
        Genome-wide transcriptional profiling and structural magnetic resonance imaging in the maternal immune activation model of neurodevelopmental disorders.
        Cereb Cortex. 2017; 27: 3397-3413
        • Meyer U.
        Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems.
        Biol Psychiatry. 2014; 75: 307-315
        • Puntener U.
        • Booth S.G.
        • Perry V.H.
        • Teeling J.L.
        Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia.
        J Neuroinflammation. 2012; 9: 146
        • van Kesteren C.F.
        • Gremmels H.
        • de Witte L.D.
        • Hol E.M.
        • Van Gool A.R.
        • Falkai P.G.
        • et al.
        Immune involvement in the pathogenesis of schizophrenia: A meta-analysis on postmortem brain studies.
        Transl Psychiatry. 2017; 7: e1075
        • Lee B.K.
        • Magnusson C.
        • Gardner R.M.
        • Blomstrom A.
        • Newschaffer C.J.
        • Burstyn I.
        • et al.
        Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders.
        Brain Behav Immun. 2015; 44: 100-105
        • Rosenkranz M.A.
        • Busse W.W.
        • Johnstone T.
        • Swenson C.A.
        • Crisafi G.M.
        • Jackson M.M.
        • et al.
        Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation.
        Proc Natl Acad Sci U S A. 2005; 102: 13319-13324
        • Eisenberger N.I.
        • Berkman E.T.
        • Inagaki T.K.
        • Rameson L.T.
        • Mashal N.M.
        • Irwin M.R.
        Inflammation-induced anhedonia: Endotoxin reduces ventral striatum responses to reward.
        Biol Psychiatry. 2010; 68: 748-754
        • Craig A.D.
        How do you feel? Interoception: The sense of the physiological condition of the body.
        Nat Rev Neurosci. 2002; 3: 655-666
        • Schultz W.
        • Dayan P.
        • Montague P.R.
        A neural substrate of prediction and reward.
        Science. 1997; 275: 1593-1599
        • Hollerman J.R.
        • Schultz W.
        Dopamine neurons report an error in the temporal prediction of reward during learning.
        Nat Neurosci. 1998; 1: 304-309
        • Harrison N.A.
        • Voon V.
        • Cercignani M.
        • Cooper E.A.
        • Pessiglione M.
        • Critchley H.D.
        A neurocomputational account of how inflammation enhances sensitivity to punishments versus rewards.
        Biol Psychiatry. 2016; 80: 73-81
        • Felger J.C.
        • Alagbe O.
        • Hu F.
        • Mook D.
        • Freeman A.A.
        • Sanchez M.M.
        • et al.
        Effects of interferon-alpha on rhesus monkeys: A nonhuman primate model of cytokine-induced depression.
        Biol Psychiatry. 2007; 62: 1324-1333
        • Kitagami T.
        • Yamada K.
        • Miura H.
        • Hashimoto R.
        • Nabeshima T.
        • Ohta T.
        Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: Role of nitric oxide as a signal crossing the blood-brain barrier.
        Brain Res. 2003; 978: 104-114
        • Felger J.C.
        • Miller A.H.
        Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise.
        Front Neuroendocrinol. 2012; 33: 315-327
        • Kamata M.
        • Higuchi H.
        • Yoshimoto M.
        • Yoshida K.
        • Shimizu T.
        Effect of single intracerebroventricular injection of alpha-interferon on monoamine concentrations in the rat brain.
        Eur Neuropsychopharmacol. 2000; 10: 129-132
        • Shuto H.
        • Kataoka Y.
        • Horikawa T.
        • Fujihara N.
        • Oishi R.
        Repeated interferon-alpha administration inhibits dopaminergic neural activity in the mouse brain.
        Brain Res. 1997; 747: 348-351
        • Pessiglione M.
        • Seymour B.
        • Flandin G.
        • Dolan R.J.
        • Frith C.D.
        Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans.
        Nature. 2006; 442: 1042-1045
        • Paulus M.P.
        • Rogalsky C.
        • Simmons A.
        • Feinstein J.S.
        • Stein M.B.
        Increased activation in the right insula during risk-taking decision making is related to harm avoidance and neuroticism.
        Neuroimage. 2003; 19: 1439-1448
        • Palminteri S.
        • Justo D.
        • Jauffret C.
        • Pavlicek B.
        • Dauta A.
        • Delmaire C.
        • et al.
        Critical roles for anterior insula and dorsal striatum in punishment-based avoidance learning.
        Neuron. 2012; 76: 998-1009
        • Capuron L.
        • Ravaud A.
        • Dantzer R.
        Timing and specificity of the cognitive changes induced by interleukin-2 and interferon-alpha treatments in cancer patients.
        Psychosom Med. 2001; 63: 376-386
        • Smith A.P.
        • Tyrrell D.A.
        • Al-Nakib W.
        • Coyle K.B.
        • Donovan C.B.
        • Higgins P.G.
        • et al.
        Effects of experimentally induced respiratory virus infections and illness on psychomotor performance.
        Neuropsychobiology. 1987; 18: 144-148
        • 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
        • Zung W.W.
        • Richards C.B.
        • Short M.J.
        Self-rating depression scale in an outpatient clinic. Further validation of the SDS.
        Arch Gen Psychiatry. 1965; 13: 508-515
        • Dantzer R.
        • Kelley K.W.
        Twenty years of research on cytokine-induced sickness behavior.
        Brain Behav Immun. 2007; 21: 153-160
        • Bluthe R.M.
        • Michaud B.
        • Poli V.
        • Dantzer R.
        Role of IL-6 in cytokine-induced sickness behavior: A study with IL-6 deficient mice.
        Physiol Behav. 2000; 70: 367-373
        • Harden L.M.
        • du Plessis I.
        • Poole S.
        • Laburn H.P.
        Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior.
        Physiol Behav. 2006; 89: 146-155
        • Pang Y.
        • Fan L.W.
        • Zheng B.
        • Cai Z.
        • Rhodes P.G.
        Role of interleukin-6 in lipopolysaccharide-induced brain injury and behavioral dysfunction in neonatal rats.
        Neuroscience. 2006; 141: 745-755
        • Goldsmith D.R.
        • Haroon E.
        • Woolwine B.J.
        • Jung M.Y.
        • Wommack E.C.
        • Harvey P.D.
        • et al.
        Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder.
        Brain Behav Immun. 2016; 56: 281-288
        • Graybiel A.M.
        • Aosaki T.
        • Flaherty A.W.
        • Kimura M.
        The basal ganglia and adaptive motor control.
        Science. 1994; 265: 1826-1831
        • Bunzeck N.
        • Duzel E.
        Absolute coding of stimulus novelty in the human substantia nigra/VTA.
        Neuron. 2006; 51: 369-379
        • Harrison N.A.
        • Cercignani M.
        • Voon V.
        • Critchley H.D.
        Effects of inflammation on hippocampus and substantia nigra responses to novelty in healthy human participants.
        Neuropsychopharmacology. 2015; 40: 831-838
        • van den Biggelaar A.H.
        • Gussekloo J.
        • de Craen A.J.
        • Frolich M.
        • Stek M.L.
        • van der Mast R.C.
        • et al.
        Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age.
        Exp Gerontol. 2007; 42: 693-701
        • Martinot M.
        • Bragulat V.
        • Artiges E.
        • Dolle F.
        • Hinnen F.
        • Jouvent R.
        • et al.
        Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation.
        Am J Psychiatry. 2001; 158: 314-316
        • Haroon E.
        • Fleischer C.C.
        • Felger J.C.
        • Chen X.
        • Woolwine B.J.
        • Patel T.
        • et al.
        Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression.
        Mol Psychiatry. 2016; 21: 1351-1357
        • Krueger J.M.
        The role of cytokines in sleep regulation.
        Curr Pharm Des. 2008; 14: 3408-3416
        • Krueger J.M.
        • Rector D.M.
        • Roy S.
        • Van Dongen H.P.
        • Belenky G.
        • Panksepp J.
        Sleep as a fundamental property of neuronal assemblies.
        Nat Rev Neurosci. 2008; 9: 910-919
        • Zielinski M.R.
        • Dunbrasky D.L.
        • Taishi P.
        • Souza G.
        • Krueger J.M.
        Vagotomy attenuates brain cytokines and sleep induced by peripherally administered tumor necrosis factor-alpha and lipopolysaccharide in mice.
        Sleep. 2013; 36 (1238A): 1227-1238
        • Sharpley A.L.
        • Cooper C.M.
        • Williams C.
        • Godlewska B.R.
        • Cowen P.J.
        Effects of typhoid vaccine on inflammation and sleep in healthy participants: A double-blind, placebo-controlled, crossover study.
        Psychopharmacology (Berl). 2016; 233: 3429-3435
        • Cohen S.
        • Doyle W.J.
        • Alper C.M.
        • Janicki-Deverts D.
        • Turner R.B.
        Sleep habits and susceptibility to the common cold.
        Arch Intern Med. 2009; 169: 62-67
        • Baglioni C.
        • Battagliese G.
        • Feige B.
        • Spiegelhalder K.
        • Nissen C.
        • Voderholzer U.
        • et al.
        Insomnia as a predictor of depression: A meta-analytic evaluation of longitudinal epidemiological studies.
        J Affect Disord. 2011; 135: 10-19
        • Cho H.J.
        • Lavretsky H.
        • Olmstead R.
        • Levin M.J.
        • Oxman M.N.
        • Irwin M.R.
        Sleep disturbance and depression recurrence in community-dwelling older adults: A prospective study.
        Am J Psychiatry. 2008; 165: 1543-1550
        • Lee E.
        • Cho H.J.
        • Olmstead R.
        • Levin M.J.
        • Oxman M.N.
        • Irwin M.R.
        Persistent sleep disturbance: A risk factor for recurrent depression in community-dwelling older adults.
        Sleep. 2013; 36: 1685-1691
        • Irwin M.R.
        • Olmstead R.
        • Breen E.C.
        • Witarama T.
        • Carrillo C.
        • Sadeghi N.
        • et al.
        Cognitive behavioral therapy and tai chi reverse cellular and genomic markers of inflammation in late-life insomnia: A randomized controlled trial.
        Biol Psychiatry. 2015; 78: 721-729
        • Irwin M.R.
        • Olmstead R.
        • Carroll J.E.
        Sleep disturbance, sleep duration, and inflammation: A systematic review and meta-analysis of cohort studies and experimental sleep deprivation.
        Biol Psychiatry. 2016; 80: 40-52
        • Irwin M.R.
        • Witarama T.
        • Caudill M.
        • Olmstead R.
        • Breen E.C.
        Sleep loss activates cellular inflammation and signal transducer and activator of transcription (STAT) family proteins in humans.
        Brain Behav Immun. 2015; 47: 86-92
        • Harshaw C.
        Interoceptive dysfunction: toward an integrated framework for understanding somatic and affective disturbance in depression.
        Psychol Bull. 2015; 141: 311-363
        • Ewing D.L.
        • Manassei M.
        • Gould van Praag C.
        • Philippides A.O.
        • Critchley H.D.
        • Garfinkel S.N.
        Sleep and the heart: Interoceptive differences linked to poor experiential sleep quality in anxiety and depression.
        Biol Psychol. 2017; 127: 163-172
        • Werner G.G.
        • Ford B.Q.
        • Mauss I.B.
        • Schabus M.
        • Blechert J.
        • Wilhelm F.H.
        High cardiac vagal control is related to better subjective and objective sleep quality.
        Biol Psychol. 2015; 106: 79-85
        • Harrison N.A.
        • Doeller C.F.
        • Voon V.
        • Burgess N.
        • Critchley H.D.
        Peripheral inflammation acutely impairs human spatial memory via actions on medial temporal lobe glucose metabolism.
        Biol Psychiatry. 2014; 76: 585-593
        • Weaver J.D.
        • Huang M.H.
        • Albert M.
        • Harris T.
        • Rowe J.W.
        • Seeman T.E.
        Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging.
        Neurology. 2002; 59: 371-378
        • Iwashyna T.J.
        • Ely E.W.
        • Smith D.M.
        • Langa K.M.
        Long-term cognitive impairment and functional disability among survivors of severe sepsis.
        JAMA. 2010; 304: 1787-1794
        • Montagne A.
        • Barnes S.R.
        • Sweeney M.D.
        • Halliday M.R.
        • Sagare A.P.
        • Zhao Z.
        • et al.
        Blood-brain barrier breakdown in the aging human hippocampus.
        Neuron. 2015; 85: 296-302
        • Ericsson A.
        • Liu C.
        • Hart R.P.
        • Sawchenko P.E.
        Type 1 interleukin-1 receptor in the rat brain: Distribution, regulation, and relationship to sites of IL-1-induced cellular activation.
        J Comp Neurol. 1995; 361: 681-698
        • Hawrylycz M.J.
        • Lein E.S.
        • Guillozet-Bongaarts A.L.
        • Shen E.H.
        • Ng L.
        • Miller J.A.
        • et al.
        An anatomically comprehensive atlas of the adult human brain transcriptome.
        Nature. 2012; 489: 391-399
        • Suzuki W.A.
        • Amaral D.G.
        Perirhinal and parahippocampal cortices of the macaque monkey: Cortical afferents.
        J Comp Neurol. 1994; 350: 497-533
        • Ban E.
        • Haour F.
        • Lenstra R.
        Brain interleukin 1 gene expression induced by peripheral lipopolysaccharide administration.
        Cytokine. 1992; 4: 48-54
        • Capuron L.
        • Lamarque D.
        • Dantzer R.
        • Goodall G.
        Attentional and mnemonic deficits associated with infectious disease in humans.
        Psychol Med. 1999; 29: 291-297
        • Reichenberg A.
        • Yirmiya R.
        • Schuld A.
        • Kraus T.
        • Haack M.
        • Morag A.
        • et al.
        Cytokine-associated emotional and cognitive disturbances in humans.
        Arch Gen Psychiatry. 2001; 58: 445-452
        • Fotuhi M.
        • Do D.
        • Jack C.
        Modifiable factors that alter the size of the hippocampus with ageing.
        Nat Rev Neurol. 2012; 8: 189-202
        • Marsland A.L.
        • Gianaros P.J.
        • Abramowitch S.M.
        • Manuck S.B.
        • Hariri A.R.
        Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults.
        Biol Psychiatry. 2008; 64: 484-490
        • Campbell S.
        • Marriott M.
        • Nahmias C.
        • MacQueen G.M.
        Lower hippocampal volume in patients suffering from depression: A meta-analysis.
        Am J Psychiatry. 2004; 161: 598-607
        • Videbech P.
        • Ravnkilde B.
        Hippocampal volume and depression: A meta-analysis of MRI studies.
        Am J Psychiatry. 2004; 161: 1957-1966
        • Airaksinen E.
        • Larsson M.
        • Lundberg I.
        • Forsell Y.
        Cognitive functions in depressive disorders: Evidence from a population-based study.
        Psychol Med. 2004; 34: 83-91
        • Gorwood P.
        • Corruble E.
        • Falissard B.
        • Goodwin G.M.
        Toxic effects of depression on brain function: Impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients.
        Am J Psychiatry. 2008; 165: 731-739
        • Sweeney J.A.
        • Kmiec J.A.
        • Kupfer D.J.
        Neuropsychologic impairments in bipolar and unipolar mood disorders on the CANTAB neurocognitive battery.
        Biol Psychiatry. 2000; 48: 674-684
        • Aaronson S.T.
        • Sears P.
        • Ruvuna F.
        • Bunker M.
        • Conway C.R.
        • Dougherty D.D.
        • et al.
        A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: Comparison of response, remission, and suicidality.
        Am J Psychiatry. 2017; 174: 640-648
        • Koopman F.A.
        • Chavan S.S.
        • Miljko S.
        • Grazio S.
        • Sokolovic S.
        • Schuurman P.R.
        • et al.
        Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis.
        Proc Natl Acad Sci U S A. 2016; 113: 8284-8289
        • Dorr A.E.
        • Debonnel G.
        Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission.
        J Pharmacol Exp Ther. 2006; 318: 890-898
        • Raison C.L.
        • Rutherford R.E.
        • Woolwine B.J.
        • Shuo C.
        • Schettler P.
        • Drake D.F.
        • et al.
        A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers.
        JAMA Psychiatry. 2013; 70: 31-41
        • Tyring S.
        • Gottlieb A.
        • Papp K.
        • Gordon K.
        • Leonardi C.
        • Wang A.
        • et al.
        Etanercept and clinical outcomes, fatigue, and depression in psoriasis: Double-blind placebo-controlled randomised phase III trial.
        Lancet. 2006; 367: 29-35
        • Kohler O.
        • Benros M.E.
        • Nordentoft M.
        • Farkouh M.E.
        • Iyengar R.L.
        • Mors O.
        • et al.
        Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: A systematic review and meta-analysis of randomized clinical trials.
        JAMA Psychiatry. 2014; 71: 1381-1391
        • Savitz J.
        • Preskorn S.
        • Teague T.K.
        • Drevets D.
        • Yates W.
        • Drevets W.
        Minocycline and aspirin in the treatment of bipolar depression: A protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial.
        BMJ Open. 2012; 2e000643
        • Moller T.
        • Bard F.
        • Bhattacharya A.
        • Biber K.
        • Campbell B.
        • Dale E.
        • et al.
        Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor.
        Glia. 2016; 64: 1788-1794
        • Chrovian C.C.
        • Rech J.C.
        • Bhattacharya A.
        • Letavic M.A.
        P2X7 antagonists as potential therapeutic agents for the treatment of CNS disorders.
        Prog Med Chem. 2014; 53: 65-100
        • Lekander M.
        • Karshikoff B.
        • Johansson E.
        • Soop A.
        • Fransson P.
        • Lundstrom J.N.
        • et al.
        Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation.
        Brain Behav Immun. 2016; 56: 34-41
        • Raz N.
        • Yang Y.
        • Dahle C.L.
        • Land S.
        Volume of white matter hyperintensities in healthy adults: Contribution of age, vascular risk factors, and inflammation-related genetic variants.
        Biochim Biophys Acta. 2012; 1822: 361-369
        • Satizabal C.L.
        • Zhu Y.C.
        • Mazoyer B.
        • Dufouil C.
        • Tzourio C.
        Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-Dijon Study.
        Neurology. 2012; 78: 720-727
        • Baune B.T.
        • Konrad C.
        • Grotegerd D.
        • Suslow T.
        • Birosova E.
        • Ohrmann P.
        • et al.
        Interleukin-6 gene (IL-6): A possible role in brain morphology in the healthy adult brain.
        J Neuroinflammation. 2012; 9: 125
        • Wohleb E.S.
        • Delpech J.C.
        Dynamic cross-talk between microglia and peripheral monocytes underlies stress-induced neuroinflammation and behavioral consequences.
        Prog Neuropsychopharmacol Biol Psychiatry. 2017; 79: 40-48