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Inflammation-related functional and structural dysconnectivity as a pathway to psychopathology

Open AccessPublished:November 08, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.11.003

      Abstract

      Findings from numerous laboratories and across neuroimaging modalities have consistently shown that exogenous administration of cytokines or inflammatory stimuli that induce cytokines disrupt circuits and networks involved in motivation and motor activity, threat detection, anxiety, interoceptive and emotional processing. While inflammatory effects on neural circuits and relevant behaviors may represent adaptive responses promoting conservation of energy and heightened vigilance during immune activation, chronically elevated inflammation may contribute to symptoms of psychiatric illnesses. Indeed, biomarkers of inflammation such as cytokines and acute phase reactants are reliably elevated in a subset of patients with unipolar or bipolar depression, anxiety-related disorders, and schizophrenia, and have been associated with differential treatment responses and poor clinical outcomes. A growing body of literature also describes higher levels of endogenous inflammatory markers and altered, typically lower functional or structural connectivity within these circuits in association with transdiagnostic symptoms like anhedonia and anxiety in psychiatric and at-risk populations. This review will present recent evidence that inflammation and its effects on the brain may serve as one molecular and cellular mechanism of dysconnectivity within anatomically and/or functionally connected cortical and subcortical regions in association with transdiagnostic symptoms. We also discuss the need to establish reproducible methods to assess inflammation-associated dysconnectivity in relation to behavior for use in translational studies or biomarker-driven clinical trials for novel pharmacological or behavioral interventions targeting inflammation or its effects on the brain.

      Key Words

      1. Inflammation in psychiatric disorders: sources and symptoms

      1a. Mechanisms and prevalence of increased inflammation in psychiatric patients

      In otherwise medically-healthy psychiatric patients, genetic predisposition may interact with environmental/lifestyle factors that contribute to low-grade inflammation including pathogens (e.g., latent infections, gut dysbiosis) and “sterile” inflammatory signals that trigger innate immune responses in the absence of pathogens (Figure 1a)(
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      Figure thumbnail gr1
      Figure 1Sources and mechanisms of inflammation and its effects on neurotransmitters and circuits that contribute to psychiatric symptoms. Mechanisms of innate immune activation and chronic low-grade inflammation, Panel A. Genetic predisposition may interact with multiple environmental and lifestyle factors that contribute to chronic low-grade inflammation, many of which are risk factors for both psychiatric disorders and major medical illnesses including psychological stress, disturbed sleep, poor diet, metabolic changes and gut dysbiosis, as well as chronic infections and environmental toxins. Innate immune cells are activated by pathogens or sterile inflammatory (e.g., DAMPs, metabolic, neuroendocrine, or oxidative stress) pathways to synthesize and release inflammatory mediators like cytokines (e.g., ILs, TNF, IFNs), which in turn induce acute phase reactants such as CRP from the liver. Acute inflammatory activity is typically resolved by homeostatic processes, but disruption of these mechanisms or prolonged immune activation can lead to chronic low-grade inflammation that impacts multiple systems including the brain. Bidirectional inflammatory processes at the blood-brain interface, Panel B. Activated innate immune cells interact with adaptive immune cells (e.g., lymphocytes), migrate into circulation, and traffic to organs and tissues including the brain. Circulating inflammatory cytokines and activated immune cells communicate with brain endothelial cells to induce other inflammatory mediators (e.g., PGE2). Inflammatory cytokines can enter the CNS via active transport or passively at circumventricular organs or openings in tight junctions of the BBB, while also signaling to the brain via vagal afferents (not shown). Microglia can be activated by inflammatory stimuli originating in the CNS or by these inflammatory signals from the periphery, and elaborate release of inflammatory mediators in the CNS like cytokines, ROS and nitrogen intermediates, as well as chemokines that further recruit peripheral inflammatory cells to perivascular regions or brain parenchyma. Inflammation also increases neuroactive metabolites from the catabolism of KYN, which is synthesized from Trp by IDO either locally in activated microglia or by macrophages followed by active transport into the brain. Inflammatory cytokines and associated oxidative molecules affect monoamine and glutamate neurotransmission, Panel C. Inflammatory cytokines and the associated release of ROS and nitrogen species can impact neuronal function through several ways including effects on neurotransmitters like monoamines and glutamate. For example, oxidation of BH4, a cofactor required for the synthesis of monoamine precursors, leads to decreased availability and release of monoamines - particularly DA, which requires BH4 for conversion of both Phe to Tyr and Tyr to L-DOPA. Evidence also exists that inflammatory cytokines can decrease expression or function of VMAT2, increase expression and activity of MATs especially the 5-HTT, and reduce expression of MARs like D2R. These effects together lead to a net decrease in synaptic monoamine availability and signaling. Inflammatory and oxidative factors also affect multiple aspects of glutamate transmission particularly by decreasing astrocytic buffering of glutamate by EAAT2, including reversing its efflux while promoting activity of the xCT to increase extracellular glutamate. Increased transport or local production of KYN in the brain and subsequent generation of neurotoxic metabolites like QUIN (a NMDAR agonist) further increase glutamate signaling including at extrasynaptic Rs, which lead to excitotoxicity and downstream generation of ROS (not shown). Peripherally administered acute and chronic inflammatory stimuli, which induce symptoms of depression and anxiety, reliably impact relevant brain regions and circuits in human neuroimaging studies, Panel D. Neuroimaging of patients chronically treated with inflammatory cytokines (e.g., IFN-α) or healthy participants administered stimuli that induce cytokines (e.g., endotoxin, vaccination) have shown that cytokines affect reward and motor-related regions and circuits, as well as those involved in threat, anxiety and emotional processing. For example, PET and MRS studies in IFN-α-treated patients reflect the impact of cytokines on neurotransmitters including reduced striatal DA availability and release as well as increased extracellular glutamate, both of which correlated with reduced motivation and low energy. Corresponding striatal microstructural as well as functional changes have included attenuated VS responses to reward anticipation/receipt and reduced FC between key regions of vmPFC and VS, after acute or chronic administration of IFN-α or other inflammatory stimuli. Inflammatory stimuli also increased neural activation of the amygdala, insula and dACC either independently or together during tasks designed to trigger emotional responses. Importantly, endotoxin also induced greater temporal variance in the amygdala at rest that correlated with lower FC within the SN as well as greater inflammation-induced anxiety. These findings on the impact of exogenous inflammatory stimuli on the brain have established a framework for the growing body of work assessing relationships between endogenous inflammatory markers and structure and function of these regions/circuits in psychiatric patients. Abbreviations: 5-HT - serotonin; 5-HTT - serotonin transporter; ACC - anterior cingulate cortex; BBB - blood-brain barrier; BH4 - tetrahydrobiopterin; CNS - central nervous system; CRP - C-reactive protein; D2R - dopamine 2 receptor; DA - dopamine; dACC - dorsal anterior cingulate cortex; DAMPs - danger-associated molecular patterns; DS - dorsal striatum; EAAT2 - excitatory amino-acid transporter 2; FC - functional connectivity; [18]FDG - fluorodeoxyglucose; [18]FDOPA - fluorodopa; IDO - indoleamine 2, 3-dioxygenase; IFN - interferon; ILs - interleukins; KYN - kynurenine; L-DOPA - levodopa; MAPK - mitogen-activated protein kinase; MARs - monoamine receptors; MATs - monoamine transporters; MRS - magnetic resonance spectroscopy; NE - norepinephrine; NFκB - nuclear factor kappa B; NLRP3 - NOD- LRR- and pyrin domain-containing protein-3; NMDAR - N-methyl-D-aspartate receptor; PET - positron emission tomography; PGE2 - prostaglandin E2; Phe - phenylalanine; QUIN - quinolinic acid; ROS - reactive oxygen species; SN - salience network; TLR - toll-like receptor; STAT - signal transducer and activator of transcription; TNF - tumor necrosis factor; Trp - tryptophan; Tyr - tyrosine; VMAT2 - vesicular monoamine transporter 2; vmPFC - ventromedial prefrontal cortex; VS - ventral striatum; xCT - cystine‐glutamate exchanger
      Peripheral-central immune crosstalk at the blood-brain interface. Elevated CRP, innate/inflammatory cytokines, and peripheral white blood cells are found in CSF (
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      ). However, lack of evidence of widespread BBB disruption (e.g., as indicated by CSF/circulating albumin, IgG ratios) observed in depression versus controls (n=106/group) or in relation to CRP (n=73)(
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      1b. Increased inflammation and transdiagnostic symptoms: cause-effect relationships
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      Endogenous inflammation, transdiagnostic symptoms, and reversal with anti-cytokine therapies. While inflammatory effects on relevant circuits and behaviors described above may represent adaptive responses promoting conservation of energy (re. reduced motivation/anhedonia, psychomotor slowing), heightened vigilance (re. threat detection, anxiety), or social/emotional adaptations during immune activation, chronically elevated inflammation may contribute to psychiatric symptoms (
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      • Raison C.L.
      The role of inflammation in depression: from evolutionary imperative to modern treatment target.
      ). Accordingly, relationships between biomarkers of low-grade inflammation and symptoms consistent with those induced by exogenous inflammatory stimuli and common to depression and other psychiatric disorders are frequently reported. For example, in medically-stable, unmedicated depressed patients, we found associations between anhedonia and both plasma CRP and clusters of inflammatory cytokines (IL-1, IL-6, TNF) and their soluble receptors in CSF (n=76)(
      • Felger J.C.
      • Haroon E.
      • Patel T.A.
      • Goldsmith D.R.
      • Wommack E.C.
      • Woolwine B.J.
      • et al.
      What does plasma CRP tell us about peripheral and central inflammation in depression?.
      ,
      • 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.
      ). Results were extended by studies reporting correlations between both T and non-T cell cytokines with anhedonia (
      • Jha M.K.
      • Miller A.H.
      • Minhajuddin A.
      • Trivedi M.H.
      Association of T and non-T cell cytokines with anhedonia: Role of gender differences.
      ), and longitudinal correlations between baseline TNF and 4-month anhedonia in depression (
      • Rengasamy M.
      • Marsland A.
      • McClain L.
      • Kovats T.
      • Walko T.
      • Pan L.
      • et al.
      Longitudinal relationships of cytokines, depression and anhedonia in depressed adolescents.
      ). We also uncovered relationships between psychomotor slowing and inflammatory markers in depression (
      • Bekhbat M.
      • Goldsmith D.R.
      • Woolwine B.J.
      • Haroon E.
      • Miller A.H.
      • Felger J.C.
      Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming.
      ,
      • 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.
      ), and numerous studies report high inflammation in schizophrenia in association with negative symptoms including motivational deficits, blunted affect, and social withdrawal (
      • Goldsmith D.R.
      • Rapaport M.H.
      Inflammation and Negative Symptoms of Schizophrenia: Implications for Reward Processing and Motivational Deficits.
      ,
      • Goldsmith D.R.
      • Massa N.
      • Pearce B.D.
      • Wommack E.C.
      • Alrohaibani A.
      • Goel N.
      • et al.
      Inflammatory markers are associated with psychomotor slowing in patients with schizophrenia compared to healthy controls.
      ). A growing literature further describes correlations between CRP/cytokines and anxiety (
      • Ye Z.
      • Kappelmann N.
      • Moser S.
      • Davey Smith G.
      • Burgess S.
      • Jones P.B.
      • et al.
      Role of inflammation in depression and anxiety: Tests for disorder specificity, linearity and potential causality of association in the UK Biobank.
      ,
      • Milaneschi Y.
      • Kappelmann N.
      • Ye Z.
      • Lamers F.
      • Moser S.
      • Jones P.B.
      • et al.
      Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts.
      ,
      • Liukkonen T.
      • Räsänen P.
      • Jokelainen J.
      • Leinonen M.
      • Järvelin M.R.
      • Meyer-Rochow V.B.
      • et al.
      The association between anxiety and C-reactive protein (CRP) levels: results from the Northern Finland 1966 birth cohort study.
      ), including longitudinally (
      • van Eeden W.A.
      • El Filali E.
      • van Hemert A.M.
      • Carlier I.V.E.
      • Penninx B.
      • Lamers F.
      • et al.
      Basal and LPS-stimulated inflammatory markers and the course of anxiety symptoms.
      ) and depression (
      • Gaspersz R.
      • Lamers F.
      • Wittenberg G.
      • Beekman A.T.F.
      • van Hemert A.M.
      • Schoevers R.A.
      • et al.
      The role of anxious distress in immune dysregulation in patients with major depressive disorder.
      ).
      The TNF antagonist infliximab reduced overall depression severity only in treatment-resistant depressed (TRD) patients with higher plasma CRP (
      • 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.
      ), and anhedonia (work and activities) was the symptom most improved followed by motor slowing (retardation) and anxiety (psychic anxiety). Recent studies similarly found that infliximab or sirukumab (anti-IL-6) preferentially reduced anhedonia in unipolar or bipolar depressed patients with evidence of increased inflammation (

      Salvadore G, Nash A, Bleys C, Hsu B, Saad Z, Gause A, et al. (2018): A Double-Blind, Placebo-Controlled, Multicenter Study of Sirukumab as Adjunctive Treatment to a Monoaminergic Antidepressant in Adults With Major Depressive Disorder, in ACNP 57th Annual Meeting: Poster Session II, Hollywood, FL. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 43:228-382.

      ,
      • Lee Y.
      • Mansur R.B.
      • Brietzke E.
      • Carmona N.E.
      • Subramaniapillai M.
      • Pan Z.
      • et al.
      Efficacy of adjunctive infliximab vs. placebo in the treatment of anhedonia in bipolar I/II depression.
      ). These cause-effect relationships indicating that transdiagnostic symptoms like anhedonia, motor slowing and anxiety can be both induced by inflammatory stimuli and reversed by cytokine antagonism, support specificity of inflammation effects on relevant brain regions/circuits that may serve as translational targets for development of treatments for patients with high inflammation (

      Miller AH, Haroon E, Felger JC (2017): Therapeutic Implications of Brain-Immune Interactions: Treatment in Translation. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 42:334-359.

      ,
      • Drevets W.C.
      • Wittenberg G.M.
      • Bullmore E.T.
      • Manji H.K.
      Immune targets for therapeutic development in depression: towards precision medicine.
      ).

      2. Impact of inflammatory stimuli on brain regions and circuits: from the clinic to the lab

      As described above, chronically administered inflammatory cytokine therapies like IFN-α cause clinically-significant depressive symptoms at high rates, and this model was used in early work examining peripheral inflammation effects on the brain. Whole-brain analyses of fluorodeoxyglucose PET in patients undergoing IFN-α therapy revealed increased resting glucose metabolism in basal ganglia (consistent with low dopamine signaling in neurologic disorders) and decreased PFC metabolism (

      Capuron L, Pagnoni G, Demetrashvili MF, Lawson DH, Fornwalt FB, Woolwine B, et al. (2007): Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 32:2384-2392.

      ,
      • Juengling F.D.
      • Ebert D.
      • Gut O.
      • Engelbrecht M.A.
      • Rasenack J.
      • Nitzsche E.U.
      • et al.
      Prefrontal cortical hypometabolism during low-dose interferon alpha treatment.
      ). These findings were subsequently linked to both low dopamine availability/release in caudate, putamen, and ventral striatum (VS: including NAc) by PET(42) and increased glutamate in basal ganglia and dorsal anterior cingulate cortex (dACC) by magnetic resonance spectroscopy (MRS)(

      Haroon E, Woolwine BJ, Chen X, Pace TW, Parekh S, Spivey JR, et al. (2014): IFN-alpha-induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 39:1777-1785.

      )(Figure 1d), all of which correlated with IFN-α-induced symptoms including reduced motivation and anergia. These clinical findings in patients during chronic IFN-α therapy indicating that peripheral inflammation impacts cortical and subcortical regions via effects on neurotransmitters like dopamine and glutamate have been confirmed and complemented by numerous laboratory human and animal studies using a variety of inflammatory stimuli, the neurobiological mechanisms of which are reviewed elsewhere (
      • Felger J.C.
      • Treadway M.T.
      Inflammation Effects on Motivation and Motor Activity: Role of Dopamine.
      ,

      Haroon E, Miller AH, Sanacora G (2017): Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 42:193-215.

      ,
      • Hunt C.
      • Macedo E.C.T.
      • Suchting R.
      • de Dios C.
      • Cuellar Leal V.A.
      • Soares J.C.
      • et al.
      Effect of immune activation on the kynurenine pathway and depression symptoms - A systematic review and meta-analysis.
      )(see Figure 1c). Relevant to a larger body of work addressing the functional consequences of exogenous inflammatory stimuli on brain regions/circuits (
      • Harrison N.A.
      Brain Structures Implicated in Inflammation-Associated Depression.
      ,
      • Felger J.C.
      Imaging the Role of Inflammation in Mood and Anxiety-related Disorders.
      ), seminal fMRI studies are briefly summarized herein (Figure 1d) as they provided a foundation for a newer literature primarily using circuit and network-based approaches to understand relationships between endogenous low-grade inflammation and altered functional and structural connectivity in psychiatric patients (Section 3).

      2a. Impact of inflammation on reward and motor regions and circuits

      Complementary to the above-described effects of inflammation on dopamine availability, functional effects of peripheral inflammation on brain regions relevant to reduced motivation and psychomotor slowing have been consistently revealed by functional MRI (fMRI) in subjects administered inflammatory cytokines (e.g., IFN-α therapy) or inflammatory stimuli (e.g., endotoxin or vaccination given in the laboratory)(
      • Felger J.C.
      • Treadway M.T.
      Inflammation Effects on Motivation and Motor Activity: Role of Dopamine.
      ). For example, chronic IFN-α treatment decreased VS neural activation to receipt of reward in association with reduced motivation (
      • 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.
      ). Similar effects on reward processing have been observed after acute endotoxin/vaccine in healthy volunteers (
      • 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.
      ,
      • 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.
      ), and complemented by vaccine effects on task-based activity in substantia nigra that correlated with psychomotor slowing and IL-6 (
      • 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.
      ,
      • 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.
      ). In addition to findings from region-focused task fMRI, whole-brain analysis revealed rapid (4-hour) IFN-α-induced microstructural changes in free water signal (consistent with edema) localized to left striatum that predicted subsequent fatigue (
      • 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.
      ). Importantly, evidence from acute IFN-α or vaccine suggests these neurotransmitter, structural and functional changes in discrete regions known to regulate motivation and motor activity contribute more broadly to inflammation effects on functional connectivity (FC) in key circuits including VS-ventromedial (vm)PFC, or as primary nodes within a global network that predicted depressive symptoms (
      • Dipasquale O.
      • Cooper E.A.
      • Tibble J.
      • Voon V.
      • Baglio F.
      • Baselli G.
      • et al.
      Interferon-alpha acutely impairs whole-brain functional connectivity network architecture - A preliminary study.
      ,
      • Harrison N.A.
      • Brydon L.
      • Walker C.
      • Gray M.A.
      • Steptoe A.
      • Critchley H.D.
      Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity.
      ).

      2b. Impact of inflammation on regions and circuits for threat, anxiety, emotional and interoceptive processing

      In addition to effects on reward and motor regions (per Section 2a/Figure 1d), peripheral inflammatory stimuli have been shown to increase neural activation of amygdala, dACC and insula (
      • Felger J.C.
      Imaging the Role of Inflammation in Mood and Anxiety-related Disorders.
      ), similar to findings reported in depression, anxiety disorders and PTSD. While analyses targeting amygdala showed higher right amygdala responses to emotional or socially threatening stimuli in relation to IFN-α or endotoxin-induced depressive or social disconnection symptoms (
      • Davies K.A.
      • Cooper E.
      • Voon V.
      • Tibble J.
      • Cercignani M.
      • Harrison N.A.
      Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms.
      ,
      • Inagaki T.K.
      • Muscatell K.A.
      • Irwin M.R.
      • Cole S.W.
      • Eisenberger N.I.
      Inflammation selectively enhances amygdala activity to socially threatening images.
      ), whole-brain-analyses have revealed inflammation-by-task-related increases in dACC, mPFC and insula activation independently or in concert with each other or amygdala (
      • Capuron L.
      • Pagnoni G.
      • Demetrashvili M.
      • Woolwine B.J.
      • Nemeroff C.B.
      • Berns G.S.
      • et al.
      Anterior cingulate activation and error processing during interferon-alpha treatment.
      ,
      • 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.
      ,
      • Eisenberger N.I.
      • Inagaki T.K.
      • Rameson L.T.
      • Mashal N.M.
      • Irwin M.R.
      An fMRI study of cytokine-induced depressed mood and social pain: the role of sex differences.
      ,
      • Kullmann J.S.
      • Grigoleit J.S.
      • Lichte P.
      • Kobbe P.
      • Rosenberger C.
      • Banner C.
      • et al.
      Neural response to emotional stimuli during experimental human endotoxemia.
      ). For example, typhoid vaccine increased task activation of an interoceptive network including mid/posterior insula as well as amygdala and dACC (
      • 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.
      ). Given the role of insula in interoception, it is not surprising this region showed increased PET resting glucose metabolism (
      • 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.
      ) and lower seed-to-voxel resting-state (rs)FC with a number of cortical regions (
      • Labrenz F.
      • Wrede K.
      • Forsting M.
      • Engler H.
      • Schedlowski M.
      • Elsenbruch S.
      • et al.
      Alterations in functional connectivity of resting state networks during experimental endotoxemia - An exploratory study in healthy men.
      ) after endotoxin. While task and seed-based analyses may bias or limit observed effects of inflammation to specific regions, a more agnostic network approach revealed reduced rsFC within a salience network (including amygdala, insula, dACC) in association with increased temporal variation of the rsFC signal only in amygdala, which in turn correlated with endotoxin-induced anxiety (
      • Labrenz F.
      • Ferri F.
      • Wrede K.
      • Forsting M.
      • Schedlowski M.
      • Engler H.
      • et al.
      Altered temporal variance and functional connectivity of BOLD signal is associated with state anxiety during acute systemic inflammation.
      ). These findings are consistent with animal studies showing rapid and behaviorally-relevant activation of amygdala by peripheral inflammatory stimuli in part via direct cytokine effects (
      • Engler H.
      • Doenlen R.
      • Engler A.
      • Riether C.
      • Prager G.
      • Niemi M.-B.
      • et al.
      Acute amygdaloid response to systemic inflammation.
      ,
      • Munshi S.
      • Rosenkranz J.A.
      Effects of Peripheral Immune Challenge on In Vivo Firing of Basolateral Amygdala Neurons in Adult Male Rats.
      ,
      • Dantzer R.
      • Konsman J.P.
      • Bluthé R.M.
      • Kelley K.W.
      Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent?.
      ), and reinforce the importance of functionally connected regions involved in interoceptive/emotional processing, vigilance/threat detection, to contribute to relevant symptoms induced by inflammation including anxiety.

      3. Structural and functional dysconnectivity in patients with high inflammation

      As discussed in Sections 1, 2, inflammation can influence neurotransmitters and key regions and circuits thought to underlie network dysfunction observed across psychiatric diagnoses (
      • Felger J.C.
      Imaging the Role of Inflammation in Mood and Anxiety-related Disorders.
      ,
      • van den Heuvel M.P.
      • Sporns O.
      A cross-disorder connectome landscape of brain dysconnectivity.
      )(Figure 1d), and may contribute to disease pathophysiology and discrete symptomologies in a subset of patients. While inflammation-associated structural and free-water changes are reported in schizophrenia (
      • Kose M.
      • Pariante C.M.
      • Dazzan P.
      • Mondelli V.
      The Role of Peripheral Inflammation in Clinical Outcome and Brain Imaging Abnormalities in Psychosis: A Systematic Review.
      ,
      • Prasad K.M.
      • Upton C.H.
      • Nimgaonkar V.L.
      • Keshavan M.S.
      Differential susceptibility of white matter tracts to inflammatory mediators in schizophrenia: an integrated DTI study.
      ,
      • Di Biase M.A.
      • Zalesky A.
      • Cetin-Karayumak S.
      • Rathi Y.
      • Lv J.
      • Boerrigter D.
      • et al.
      Large-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals.
      ,
      • Wang Y.
      • Wei Y.
      • Edmiston E.K.
      • Womer F.Y.
      • Zhang X.
      • Duan J.
      • et al.
      Altered structural connectivity and cytokine levels in Schizophrenia and Genetic high-risk individuals: Associations with disease states and vulnerability.
      ), studies contributing to our evolving understanding of relationships between endogenous inflammation and brain activity or FC relevant to transdiagnostic symptoms in psychiatric disorders have focused primarily on depression or bipolar disorder and taken hypothesis-driven, symptom-focused approaches to examine relationships between inflammation and frontostriatal, amygdala-prefrontal, and interoceptive circuits/networks (Table 1). Accordingly, findings are presented with a circuit/symptom focus. As relationships between inflammatory markers in psychiatric patients and low rsFC have emerged as the most consistent findings for inflammation-associated dysconnectivity, with potential for translational use as a reliable brain biomarker of inflammation, these studies are highlighted in Figure 2.
      Table 1Summary of studies assessing relationships between endogenous inflammation and functional or structural neuroimaging outcomes in the context of significant psychiatric symptoms or diagnoses.
      StudyPopulationInflammatory MarkersOutcomeBrain Region/White Matter Tract
      Resting State Functional Connectivity and Supporting fMRI Studies
      Circuits and Regions Relevant to Reduced Motivation or Psychomotor Slowing
      Felger et al., 2016 (
      • 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.
      )
      MDDCRP↓ seed-to-voxel and seed-to-ROI, resting-state FC(
      • Berk M.
      • Williams L.J.
      • Jacka F.N.
      • O'Neil A.
      • Pasco J.A.
      • Moylan S.
      • et al.
      So depression is an inflammatory disease, but where does the inflammation come from?.
      ) Left VS-vmPFC

      (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      ) Dorsal striatum and vmPFC, presupplementary motor area
      Yin et al., 2019 (
      • Yin L.
      • Xu X.
      • Chen G.
      • Mehta N.D.
      • Haroon E.
      • Miller A.H.
      • et al.
      Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.
      )
      MDDCRP↓ Voxel-wise GBC and PBA of 100 ROIs, resting-state FCNetwork with central hubs in vmPFC followed by VS
      Mehta et al., 2020 (
      • Mehta N.D.
      • Stevens J.S.
      • Li Z.
      • Gillespie C.F.
      • Fani N.
      • Michopoulos V.
      • et al.
      Inflammation, reward circuitry and symptoms of anhedonia and PTSD in trauma-exposed women.
      )
      Trauma-exposed women with or without clinically significant PTSD symptomsCRP, inflammatory cytokine composite score↓ seed-to-ROI, resting-state FCVS-vmPFC
      Tang et al., 2021 (
      • Tang G.
      • Chen P.
      • Chen G.
      • Zhong S.
      • Gong J.
      • Zhong H.
      • et al.
      Inflammation is correlated with abnormal functional connectivity in unmedicated bipolar depression: an independent component analysis study of resting-state fMRI.
      )
      BD (current episode depressed)IL-8↓ ICA, resting-state FCRight precentral gyrus (somatomotor network)
      Tseng et al., 2021 (
      • Tseng H.H.
      • Chang H.H.
      • Wei S.Y.
      • Lu T.H.
      • Hsieh Y.T.
      • Yang Y.K.
      • et al.
      Peripheral inflammation is associated with dysfunctional corticostriatal circuitry and executive dysfunction in bipolar disorder patients.
      )
      BD (euthymic)CRP↑ seed-to-voxel, resting-state FCRight dorsal caudal putamen- middle orbitofrontal gyrus
      Rengasamy et al, 2022 (
      • Rengasamy M.
      • Brundin L.
      • Griffo A.
      • Panny B.
      • Capan C.
      • Forton C.
      • et al.
      Cytokine and Reward Circuitry Relationships in Treatment-Resistant Depression.
      )
      TRDIL-6↓ seed-to-ROI, resting-state FCLeft VS-vmPFC
      Haroon et al., 2018 (
      • Haroon E.
      • Chen X.
      • Li Z.
      • Patel T.
      • Woolwine B.J.
      • Hu X.P.
      • et al.
      Increased inflammation and brain glutamate define a subtype of depression with decreased regional homogeneity, impaired network integrity, and anhedonia.
      )
      MDDCRP↓ local and network, resting-state ReHo functional integrityLeft basal ganglia and network varying by levels of CRP and MRS glutamate
      Bradley et al., 2019 (
      • Bradley K.A.
      • Stern E.R.
      • Alonso C.M.
      • Xie H.
      • Kim-Schulze S.
      • Gabbay V.
      Relationships between neural activation during a reward task and peripheral cytokine levels in youth with diverse psychiatric symptoms.
      )
      Adolescents presenting with clinically significant psychiatric symptomsInflammatory composite factors↓ activation to reward attainment (
      • Berk M.
      • Williams L.J.
      • Jacka F.N.
      • O'Neil A.
      • Pasco J.A.
      • Moylan S.
      • et al.
      So depression is an inflammatory disease, but where does the inflammation come from?.
      ) and anticipation (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      )
      (
      • Berk M.
      • Williams L.J.
      • Jacka F.N.
      • O'Neil A.
      • Pasco J.A.
      • Moylan S.
      • et al.
      So depression is an inflammatory disease, but where does the inflammation come from?.
      ) Basal ganglia (ROI), angular gyrus (whole-brain)

      (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      ) Precuneus/PCC (whole-brain)
      Liu et al., 2020 (
      • Liu Q.
      • Ely B.
      • Simkovic S.
      • Tao A.
      • Wolchok R.
      • Alonso C.M.
      • et al.
      Correlates of C-reactive protein with neural reward circuitry in adolescents with psychiatric symptoms.
      )
      Adolescents presenting with clinically significant psychiatric symptomsCRP↑ activation to reward attainment (
      • Berk M.
      • Williams L.J.
      • Jacka F.N.
      • O'Neil A.
      • Pasco J.A.
      • Moylan S.
      • et al.
      So depression is an inflammatory disease, but where does the inflammation come from?.
      )

      ↓ activation to reward anticipation (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      )

      ↑ activation to positive prediction error (
      • Costello H.
      • Gould R.L.
      • Abrol E.
      • Howard R.
      Systematic review and meta-analysis of the association between peripheral inflammatory cytokines and generalised anxiety disorder.
      )
      (
      • Berk M.
      • Williams L.J.
      • Jacka F.N.
      • O'Neil A.
      • Pasco J.A.
      • Moylan S.
      • et al.
      So depression is an inflammatory disease, but where does the inflammation come from?.
      ) Visual and dorsal attention networks (whole-brain)

      (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      ) dACC (ROI)

      (
      • Costello H.
      • Gould R.L.
      • Abrol E.
      • Howard R.
      Systematic review and meta-analysis of the association between peripheral inflammatory cytokines and generalised anxiety disorder.
      ) NAc (ROI)
      Burrows et al., 2021 (
      • Burrows K.
      • Stewart J.L.
      • Kuplicki R.
      • Figueroa-Hall L.
      • Spechler P.A.
      • Zheng H.
      • et al.
      Elevated peripheral inflammation is associated with attenuated striatal reward anticipation in major depressive disorder.
      )
      MDDCRP↓ activation to anticipation of small rewardsDorsal caudate, thalamus, left insula, left precuneus (whole-brain)
      Costi et al., 2021 (

      Costi S, Morris LS, Collins A, Fernandez NF, Patel M, Xie H, et al. (2021): Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia. Translational psychiatry. 11:565-565.

      )
      MDD and healthy adultsStimulated blood immune markers↓ activation to reward anticipationVS (ROI)
      Circuits and Regions Relevant to Threat, Anxiety and Emotional Processing
      Mehta et al., 2018 (
      • Mehta N.D.
      • Haroon E.
      • Xu X.
      • Woolwine B.J.
      • Li Z.
      • Felger J.C.
      Inflammation negatively correlates with amygdala-ventromedial prefrontal functional connectivity in association with anxiety in patients with depression: Preliminary results.
      )
      MDD with or without comorbid anxiety disorders or PTSDCRP, IL-6, IL-1ra↓ ROI-to-voxel and ROI-to-ROI, resting-state FC(
      • Berk M.
      • Williams L.J.
      • Jacka F.N.
      • O'Neil A.
      • Pasco J.A.
      • Moylan S.
      • et al.
      So depression is an inflammatory disease, but where does the inflammation come from?.
      ) Right amygdala-vmPFC

      (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      ) Right amygdala-left precentral gyrus
      Gong et al., 2022 (
      • Gong J.
      • Chen G.
      • Chen F.
      • Zhong S.
      • Chen P.
      • Zhong H.
      • et al.
      Association between resting-state functional connectivity of amygdala subregions and peripheral pro-inflammation cytokines levels in bipolar disorder.
      )
      BD (>75% depressive episode)TNF↓ seed-to-voxel, resting-state FC(
      • Berk M.
      • Williams L.J.
      • Jacka F.N.
      • O'Neil A.
      • Pasco J.A.
      • Moylan S.
      • et al.
      So depression is an inflammatory disease, but where does the inflammation come from?.
      ) Right amygdala-bilateral medial PFC

      (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      ) Left amygdala-left temporal pole
      Mehta et al., 2022 (
      • Mehta N.D.
      • Stevens J.S.
      • Li Z.
      • Fani N.
      • Gillespie C.F.
      • Ravi M.
      • et al.
      Inflammation, amygdala-ventromedial prefrontal functional connectivity and symptoms of anxiety and PTSD in African American women recruited from an inner-city hospital: Preliminary results.
      )
      Trauma-exposed women with or without clinically significant PTSD symptomsCRP, inflammatory cytokine composite score↓ ROI-to-ROI, resting-state FCRight amygdala-vmPFC
      Savitz et al., 2013 (
      • 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.
      )
      MDDExpression of immune-related PBMC genes↑ activation to sad vs happy facesAmygdala, left hippocampus, and vmPFC (ROIs from whole-brain MDD > HC)
      Mocking et al, 2017 (
      • RJT Mocking
      • Nap T.S.
      • Westerink A.M.
      • Assies J.
      • Vaz F.M.
      • Koeter M.W.J.
      • et al.
      Biological profiling of prospective antidepressant response in major depressive disorder: Associations with (neuro)inflammation, fatty acid metabolism, and amygdala-reactivity.
      )
      MDDCRPNo association with reactivity to negative facesBilateral amygdala (ROI)
      Poletti et al., 2017 (
      • Poletti S.
      • de Wit H.
      • Mazza E.
      • Wijkhuijs A.J.M.
      • Locatelli C.
      • Aggio V.
      • et al.
      Th17 cells correlate positively to the structural and functional integrity of the brain in bipolar depression and healthy controls.
      )
      BD (current episode depressed)T regulatory cells↓ activation to negative vs. positive stimuliRight dorsolateral PFC/inferior frontal gyrus (whole-brain)
      Conejero et al., 2019 (
      • Conejero I.
      • Jaussent I.
      • Cazals A.
      • Thouvenot E.
      • Mura T.
      • Le Bars E.
      • et al.
      Association between baseline pro-inflammatory cytokines and brain activation during social exclusion in patients with vulnerability to suicide and depressive disorder.
      )
      Women with history of MDD and/or SA and healthy controlsIL-1β, IL-2↓ activation related to IL-1β (
      • Berk M.
      • Williams L.J.
      • Jacka F.N.
      • O'Neil A.
      • Pasco J.A.
      • Moylan S.
      • et al.
      So depression is an inflammatory disease, but where does the inflammation come from?.
      )

      ↑ activation related to IL-2 (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      ) during social exclusion
      (
      • Berk M.
      • Williams L.J.
      • Jacka F.N.
      • O'Neil A.
      • Pasco J.A.
      • Moylan S.
      • et al.
      So depression is an inflammatory disease, but where does the inflammation come from?.
      ) Right orbitofrontal cortex

      (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      ) Right orbitofrontal cortex, insula and ACC (ROI)
      Boukezzi et al., 2022 (
      • Boukezzi S.
      • Costi S.
      • Shin L.M.
      • Kim-Schulze S.
      • Cathomas F.
      • Collins A.
      • et al.
      Exaggerated amygdala response to threat and association with immune hyperactivity in depression.
      )
      MDDStimulated blood immune markers↑ activation to fear vs happy facesAmygdala (ROI)
      Interoceptive, Default Mode and other Large-Scale Networks
      Chen et al., 2020 (
      • Chen P.
      • Chen F.
      • Chen G.
      • Zhong S.
      • Gong J.
      • Zhong H.
      • et al.
      Inflammation is associated with decreased functional connectivity of insula in unmedicated bipolar disorder.
      )
      BD (current episode depressed)IL-6↓ seed-to-voxel, resting-state FCRight posterior insula-left postcentral gyrus
      Aruldass et al., 2021 (
      • Aruldass A.R.
      • Kitzbichler M.G.
      • Morgan S.E.
      • Lim S.
      • Lynall M.-E.
      • Turner L.
      • et al.
      Dysconnectivity of a brain functional network was associated with blood inflammatory markers in depression.
      )
      MDDCRP, IL-6, neutrophils, CD4+ T-cells↓ NBS of 8 networks, resting-state FCWithin insular/frontal opercular cortex (VAN) and the posterior cingulate cortex (DMN)
      Kitzbichler et al., 2021 (
      • Kitzbichler M.G.
      • Aruldass A.R.
      • Barker G.J.
      • Wood T.C.
      • Dowell N.G.
      • Hurley S.A.
      • et al.
      Peripheral inflammation is associated with micro-structural and functional connectivity changes in depression-related brain networks.
      )
      MDDCRP↓↑ PBA of 360 cortical and 16 subcortical ROIs, resting-state FCLower within DMN, higher DMN-hippocampus, in association with PD free water edema signal
      King et al., 2021 (
      • King S.
      • Holleran L.
      • Mothersill D.
      • Patlola S.
      • Rokita K.
      • McManus R.
      • et al.
      Early life Adversity, functional connectivity and cognitive performance in Schizophrenia: The mediating role of IL-6.
      )
      SZIL-6↓ seed-to-voxel, resting-state FCLeft lateral parietal cortex-precuneus of DMN
      Beckmann et al., 2022 (
      • Beckmann F.E.
      • Seidenbecher S.
      • Metzger C.D.
      • Gescher D.M.
      • Carballedo A.
      • Tozzi L.
      • et al.
      C-reactive protein is related to a distinct set of alterations in resting-state functional connectivity contributing to a differential pathophysiology of major depressive disorder.
      )
      MDDCRP↑ seed-based analysis of 5 networks, resting-state FCInternetwork DMN to AN
      Structural Connectivity Studies
      Prasad et al., 2015 (
      • Prasad K.M.
      • Upton C.H.
      • Nimgaonkar V.L.
      • Keshavan M.S.
      Differential susceptibility of white matter tracts to inflammatory mediators in schizophrenia: an integrated DTI study.
      )
      SZCRP, IL-6↓ FA, ↑ RDInferior longitudinal fasciculus, inferior fronto-occipital fasciculus, forceps major (RD to IL-6 only)
      Benedetti et al., 2016 (
      • Benedetti F.
      • Poletti S.
      • Hoogenboezem T.A.
      • Mazza E.
      • Ambrée O.
      • de Wit H.
      • et al.
      Inflammatory cytokines influence measures of white matter integrity in Bipolar Disorder.
      )
      BD (current episode depressed)TNF, IL-8, IFN-γ↓ FA ↑ RDCorpus callosum, cingulum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi, uncinate, forceps, corona radiata, thalamic radiation, internal capsule
      Sugimoto et al., 2018 (
      • Sugimoto K.
      • Kakeda S.
      • Watanabe K.
      • Katsuki A.
      • Ueda I.
      • Igata N.
      • et al.
      Relationship between white matter integrity and serum inflammatory cytokine levels in drug-naive patients with major depressive disorder: diffusion tensor imaging study using tract-based spatial statistics.
      )
      MDDIL-1β↓ FAInferior fronto-occipital fasciculi, left uncinate fasciculus
      Wang et al., 2020 (
      • Wang Y.
      • Wei Y.
      • Edmiston E.K.
      • Womer F.Y.
      • Zhang X.
      • Duan J.
      • et al.
      Altered structural connectivity and cytokine levels in Schizophrenia and Genetic high-risk individuals: Associations with disease states and vulnerability.
      )
      SZIL-6↓ FAGenu and body of corpus callosum, anterior/posterior limbs of internal capsule
      Lim et al., 2021 (
      • Lim J.
      • Sohn H.
      • Kwon M.S.
      • Kim B.
      White Matter Alterations Associated with Pro-inflammatory Cytokines in Patients with Major Depressive Disorder.
      )
      MDDTNF↓ FAGenu of corpus callosum, left anterior and superior corona radiata
      Thomas et al., 2021 (

      Thomas M, Savitz J, Zhang Y, Burrows K, Smith R, Figueroa-Hall L, et al. (2021): Elevated Systemic Inflammation Is Associated with Reduced Corticolimbic White Matter Integrity in Depression. Life (Basel). 12.

      )
      MDDCRP↓ QACorticostriatal tracts, thalamic radiations, inferior longitudinal fasciculi, corpus callosum, cingulum, and left superior longitudinal fasciculus
      AN - affective network; BD - bipolar disorder; CRP - C-reactive protein; dACC - dorsal anterior cingulate cortex; DMN - default mode network; FA - fractional anisotropy; FC - functional connectivity; GBC - global brain connectivity; HC - healthy controls; IFN - interferon; IL - interleukin; L-DOPA - levodopa; MDD - major depressive disorder; MRS - magnetic resonance spectroscopy; NAc - nucleus accumbens; NBS - network-based statistics; PBA - parcellation-based analysis; PBMC - peripheral blood mononuclear cells; PCC - posterior cingulate cortex; PD - proton density; PTSD - post-traumatic stress disorder; QA - quantitative anisotropy; ra - receptor antagonist; RD - radial diffusivity; ReHo - regional homogeneity; SA - suicide attempt; SZ - schizophrenia; TNF - tumor necrosis factor; TRD - treatment-resistant depression; VAN - ventral attention network; vmPFC - ventromedial prefrontal cortex; VS - ventral striatum
      Figure thumbnail gr2
      Figure 2Inflammation-associated resting-state functional “dysconnectivity” in key circuits and networks that contribute to psychiatric disorders. Summary of key studies from an emerging literature describing associations between circulating biomarkers of inflammation, such as inflammatory cytokines and the acute phase reactant CRP, in patients with depression or other psychiatric illnesses and low resting-state functional connectivity (rsFC) in frontostriatal circuits regulating motivation or motor activity, amygdala-prefrontal circuits involved in fear, threat and anxiety, and circuits/networks involved in interoceptive and emotional processing, all of which may contribute to transdiagnostic symptoms in patients with psychiatric disorders. A host of medical, environmental, and lifestyle factors contribute to innate immune activation in patients with depression and other psychiatric disorders. Peripheral immune cells like monocytes and T cells activate inflammatory signaling pathways and undergo a metabolic reprograming to facilitate the release of cytokines and cell trafficking to the brain. Inflammatory cytokines produced in the periphery and CNS can impact neural activation and functional connectivity within key brain regions, circuits, and networks relevant to psychiatric disorders through effects on neurotransmitters like dopamine and glutamate, or structural changes like reduced white matter integrity. Abbreviations: BD - bipolar disorder; CRP - C-reactive protein; DMN - default mode network; FA - fractional anisotropy; FC - functional connectivity; IFN - interferon; IL - interleukin; Jak-Stat - Janus kinase-Signal transducer and activator of transcription; MDD - major depressive disorder; MRS - magnetic resonance spectroscopy; NAc - nucleus accumbens; NFκB - nuclear factor kappa B; PCC - posterior cingulate cortex; PD - proton density; pSMA - pre-supplementary motor area; PTSD - post-traumatic stress disorder; TNF - tumor necrosis factor; TRD - treatment-resistant depression; VAN - ventral attention network; vmPFC - ventromedial prefrontal cortex; VS - ventral striatum
      Inflammation and low rsFC in non-psychiatric populations: risk factors across the lifespan. As our discussion focuses on endogenous inflammation and rsFC in the context of psychiatric disorders, it is worthy to mention representative studies from a similar body of work in non-psychiatric populations. Consistent with the above-described effects of peripheral inflammation on regions and circuits involved in emotion regulation (Section 2b), a composite index of CRP/inflammatory cytokines, or numbers of classical monocytes, associated with low rsFC in an emotion-regulation network in cohorts of at-risk African American (AA) youth (
      • Nusslock R.
      • Brody G.H.
      • Armstrong C.C.
      • Carroll A.L.
      • Sweet L.H.
      • Yu T.
      • et al.
      Higher Peripheral Inflammatory Signaling Associated With Lower Resting-State Functional Brain Connectivity in Emotion Regulation and Central Executive Networks.
      ). Associations between cytokines (TNF) and altered rsFC in adolescents also extended to other inflammation-sensitive regions including right amygdala and left VS (
      • Swartz J.R.
      • Carranza A.F.
      • Tully L.M.
      • Knodt A.R.
      • Jiang J.
      • Irwin M.R.
      • et al.
      Associations between peripheral inflammation and resting state functional connectivity in adolescents.
      ). In adults, IL-6 partially mediated relationships between childhood abuse and lower amygdala-vmPFC rsFC (
      • Kraynak T.E.
      • Marsland A.L.
      • Hanson J.L.
      • Gianaros P.J.
      Retrospectively reported childhood physical abuse, systemic inflammation, and resting corticolimbic connectivity in midlife adults.
      ), and an inflammatory cytokine composite related to low salience, default mode network (DMN), and central executive inter-network rsFC in association with sub-clinical PTSD symptoms in stress-exposed firefighters (
      • Kim J.
      • Yoon S.
      • Lee S.
      • Hong H.
      • Ha E.
      • Joo Y.
      • et al.
      A double-hit of stress and low-grade inflammation on functional brain network mediates posttraumatic stress symptoms.
      ). Finally, an inflammatory cell index (neutrophil/lymphocyte ratio) in older adults negatively correlated with rsFC within regions of vmPFC in relation to geriatric depression symptoms (
      • McIntosh R.C.
      • Lobo J.
      • Paparozzi J.
      • Goodman Z.
      • Kornfeld S.
      • Nomi J.
      Neutrophil to lymphocyte ratio is a transdiagnostic biomarker of depression and structural and functional brain alterations in older adults.
      ). These findings, together with the impact of inflammatory stimuli on the brain (Section 2), suggest that inflammation-effects on FC within sensitive regions/circuits serve as potential brain mechanisms of the frequently reported associations between inflammatory markers and psychiatric symptoms in individuals exposed to risk factors like stress, early life adversity, and aging (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • et al.
      Chronic inflammation in the etiology of disease across the life span.
      ,
      • Miller A.H.
      • Raison C.L.
      The role of inflammation in depression: from evolutionary imperative to modern treatment target.
      ), and support these pathways as mechanisms of inflammation-related dysconnectivity in psychiatric patients.

      3a. Frontostriatal circuits and transdiagnostic symptoms of reduced motivation and psychomotor slowing

      Inflammation and low rsFC in reward and motor circuits. Similar to the effects of exogenous inflammatory stimuli on reward-relevant regions (Section 2a, Figure 1d), we and other have found relationships between endogenous inflammation in psychiatric patients and low rsFC in frontostriatal circuits including VS-vmPFC, a classic reward circuit found to be disrupted in depression and other psychiatric disorders (
      • Kaiser R.H.
      • Andrews-Hanna J.R.
      • Wager T.D.
      • Pizzagalli D.A.
      Large-Scale Network Dysfunction in Major Depressive Disorder: A Meta-analysis of Resting-State Functional Connectivity.
      ,
      • Whitton A.E.
      • Treadway M.T.
      • Pizzagalli D.A.
      Reward processing dysfunction in major depression, bipolar disorder and schizophrenia.
      ). For example, negative associations between plasma CRP and left VS-vmPFC rsFC were observed using both seed-to-voxel-wise and targeted seed-to-ROI approaches in medically-stable, unmedicated depressed patients (n=48), whereby lower VS-vmPFC rsFC in turn correlated with and mediated relationships between CRP and anhedonia (
      • 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.
      ). Frontostriatal rsFC also negatively associated with inflammatory cytokines and their soluble receptors (
      • 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.
      ). These relationships in depression were corroborated by parcellation-based network analyses whereby primary (vmPFC) and secondary (VS, as anterior caudate) hubs, along with multiple other edges of a 63-feature network of CRP-associated dysconnectivity, highly predicted anhedonia symptoms in support vector regression (
      • Yin L.
      • Xu X.
      • Chen G.
      • Mehta N.D.
      • Haroon E.
      • Miller A.H.
      • et al.
      Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.
      ). Negative associations between inflammatory markers and left VS-vmPFC rsFC were replicated by Rengasamy et al. for IL-6 in TRD (
      • Rengasamy M.
      • Brundin L.
      • Griffo A.
      • Panny B.
      • Capan C.
      • Forton C.
      • et al.
      Cytokine and Reward Circuitry Relationships in Treatment-Resistant Depression.
      ), and in our group for CRP in association with anhedonia in trauma-exposed inner-city AA women, while a composite of inflammatory cytokines and their receptors (
      • Felger J.C.
      • Haroon E.
      • Patel T.A.
      • Goldsmith D.R.
      • Wommack E.C.
      • Woolwine B.J.
      • et al.
      What does plasma CRP tell us about peripheral and central inflammation in depression?.
      ) only correlated with rsFC in women with significant PTSD symptoms (
      • Mehta N.D.
      • Stevens J.S.
      • Li Z.
      • Gillespie C.F.
      • Fani N.
      • Michopoulos V.
      • et al.
      Inflammation, reward circuitry and symptoms of anhedonia and PTSD in trauma-exposed women.
      ). Relevant to risk factors for associations between high inflammation and low rsFC, early-life adversity modified these relationships whereby severity of childhood maltreatment predicted stronger negative cytokine-rsFC associations in both studies (
      • Rengasamy M.
      • Brundin L.
      • Griffo A.
      • Panny B.
      • Capan C.
      • Forton C.
      • et al.
      Cytokine and Reward Circuitry Relationships in Treatment-Resistant Depression.
      ,
      • Mehta N.D.
      • Stevens J.S.
      • Li Z.
      • Gillespie C.F.
      • Fani N.
      • Michopoulos V.
      • et al.
      Inflammation, reward circuitry and symptoms of anhedonia and PTSD in trauma-exposed women.
      ).
      Consistent with inflammatory stimuli effects on motor activity (
      • Felger J.C.
      • Treadway M.T.
      Inflammation Effects on Motivation and Motor Activity: Role of Dopamine.
      ), endogenous inflammation also correlated with dysconnectivity within corticostriatal circuits involving cognitive and motor regions of dorsal striatum. For example, we found negative relationships between CRP and rsFC for dorsal caudate and dorsal caudal putamen with vmPFC and/or presupplementary motor area in association with psychomotor slowing in depression (
      • 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.
      ). These relationships along with additional rsFC features identified in network analyses highly predicted psychomotor slowing (
      • Yin L.
      • Xu X.
      • Chen G.
      • Mehta N.D.
      • Haroon E.
      • Miller A.H.
      • et al.
      Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.
      ). Similar relationships have been seen in depressed, but not euthymic (
      • Tseng H.H.
      • Chang H.H.
      • Wei S.Y.
      • Lu T.H.
      • Hsieh Y.T.
      • Yang Y.K.
      • et al.
      Peripheral inflammation is associated with dysfunctional corticostriatal circuitry and executive dysfunction in bipolar disorder patients.
      ), bipolar disorder patients including negative correlations between IL-8 and rsFC of right precentral gyrus within a somatomotor network, as demonstrated by Tang et al. with independent component analysis (ICA)(
      • Tang G.
      • Chen P.
      • Chen G.
      • Zhong S.
      • Gong J.
      • Zhong H.
      • et al.
      Inflammation is correlated with abnormal functional connectivity in unmedicated bipolar depression: an independent component analysis study of resting-state fMRI.
      ).
      Complementary task fMRI, neurotransmitter, and structural studies. Relationships between endogenous inflammation and low rsFC in frontostriatal reward and motor circuits in patients are complemented by a study from Burrows et al. showing decreased activation of dorsal caudate, thalamus, left insula, and left precuneus in anticipation of small wins in depression with higher CRP (>3 mg/L)(
      • Burrows K.
      • Stewart J.L.
      • Kuplicki R.
      • Figueroa-Hall L.
      • Spechler P.A.
      • Zheng H.
      • et al.
      Elevated peripheral inflammation is associated with attenuated striatal reward anticipation in major depressive disorder.
      ). Costi et al. also found an endotoxin-stimulated inflammatory factor to negatively correlate with VS response to reward anticipation in association with anhedonia in depression (

      Costi S, Morris LS, Collins A, Fernandez NF, Patel M, Xie H, et al. (2021): Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia. Translational psychiatry. 11:565-565.

      ). Relationships between either CRP or inflammatory cytokine factors and reward anticipation/attainment in striatal and prefrontal regions were similarly seen in adolescents with clinically-significant psychiatric symptoms (
      • Liu Q.
      • Ely B.
      • Simkovic S.
      • Tao A.
      • Wolchok R.
      • Alonso C.M.
      • et al.
      Correlates of C-reactive protein with neural reward circuitry in adolescents with psychiatric symptoms.
      ,
      • Bradley K.A.
      • Stern E.R.
      • Alonso C.M.
      • Xie H.
      • Kim-Schulze S.
      • Gabbay V.
      Relationships between neural activation during a reward task and peripheral cytokine levels in youth with diverse psychiatric symptoms.
      ). These associations between inflammation and low activity or rsFC within frontostriatal circuits may involve its effects on neurotransmitters like dopamine and glutamate (
      • Felger J.C.
      • Treadway M.T.
      Inflammation Effects on Motivation and Motor Activity: Role of Dopamine.
      ,

      Haroon E, Miller AH, Sanacora G (2017): Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 42:193-215.

      )(Figure 1c,d). Plasma and CSF CRP in medically-stable, unmedicated depressed patients associated with left basal ganglia glutamate (using single-voxel MRS)(
      • 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.
      ), which jointly identified a larger network of low regional homogeneity (“ReHo,” concordance of oscillatory activity in neighboring MRS voxels, including a reward-related subnetwork)(
      • Haroon E.
      • Chen X.
      • Li Z.
      • Patel T.
      • Woolwine B.J.
      • Hu X.P.
      • et al.
      Increased inflammation and brain glutamate define a subtype of depression with decreased regional homogeneity, impaired network integrity, and anhedonia.
      ), and correlated with anhedonia and psychomotor slowing. Regarding links to dopamine, we recently reported that acute challenge with its precursor levodopa (which rapidly increases dopamine availability) improved left VS-vmPFC rsFC only in depressed patients with higher CRP (>2 mg/L) in association with higher task-FC during reward anticipation and levodopa-induced decreases in anhedonia (
      • Bekhbat M.
      • Li Z.
      • Mehta N.D.
      • Treadway M.T.
      • Lucido M.J.
      • Woolwine B.J.
      • et al.
      Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study.
      ). In addition to neurotransmitter influence on functional circuits/networks, inflammation may impact rsFC through effects on structural connectivity as relationships between CRP/cytokines and low white matter integrity (quantitative and fractional anisotropy) have been observed in depressed and bipolar patients in numerous important tracts including corticostriatal and thalamic radiations connecting cortical and subcortical structures (

      Thomas M, Savitz J, Zhang Y, Burrows K, Smith R, Figueroa-Hall L, et al. (2021): Elevated Systemic Inflammation Is Associated with Reduced Corticolimbic White Matter Integrity in Depression. Life (Basel). 12.

      ,
      • Sugimoto K.
      • Kakeda S.
      • Watanabe K.
      • Katsuki A.
      • Ueda I.
      • Igata N.
      • et al.
      Relationship between white matter integrity and serum inflammatory cytokine levels in drug-naive patients with major depressive disorder: diffusion tensor imaging study using tract-based spatial statistics.
      ,
      • Lim J.
      • Sohn H.
      • Kwon M.S.
      • Kim B.
      White Matter Alterations Associated with Pro-inflammatory Cytokines in Patients with Major Depressive Disorder.
      ,
      • Benedetti F.
      • Poletti S.
      • Hoogenboezem T.A.
      • Mazza E.
      • Ambrée O.
      • de Wit H.
      • et al.
      Inflammatory cytokines influence measures of white matter integrity in Bipolar Disorder.
      ).

      3b. Amygdala-prefrontal circuits involved in threat detection, anxiety, and emotional processing

      Inflammation and low amygdala-PFC rsFC. In addition to effects on motivation and motor activity, inflammatory stimuli induce symptoms of anxiety in the context of heightened reactivity and low rsFC of amygdala and prefrontal regions (
      • Lasselin J.
      • Elsenbruch S.
      • Lekander M.
      • Axelsson J.
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      Mood disturbance during experimental endotoxemia: Predictors of state anxiety as a psychological component of sickness behavior.
      ,
      • Inagaki T.K.
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      Inflammation selectively enhances amygdala activity to socially threatening images.
      ,
      • Labrenz F.
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      • et al.
      Alterations in functional connectivity of resting state networks during experimental endotoxemia - An exploratory study in healthy men.
      ,
      • Labrenz F.
      • Ferri F.
      • Wrede K.
      • Forsting M.
      • Schedlowski M.
      • Engler H.
      • et al.
      Altered temporal variance and functional connectivity of BOLD signal is associated with state anxiety during acute systemic inflammation.
      )(Section 2, Figure 1d), consistent with reports of associations between inflammation and low rsFC in this circuitry in psychiatric patients. Accordingly, we found associations between endogenous inflammatory markers, plasma CRP and inflammatory cytokines and their soluble receptors, and low right amygdala-vmPFC rsFC in medically-stable, unmedicated patients with a primary diagnosis of depression (
      • Mehta N.D.
      • Haroon E.
      • Xu X.
      • Woolwine B.J.
      • Li Z.
      • Felger J.C.
      Inflammation negatively correlates with amygdala-ventromedial prefrontal functional connectivity in association with anxiety in patients with depression: Preliminary results.
      ). Right amygdala-vmPFC rsFC in turn negatively correlated with and mediated relationships between CRP and symptoms of anxiety, and these findings were strongest in patients with co-morbid anxiety disorders or PTSD. Relationships between CRP or cytokines and rsFC between right amygdala and mPFC/vmPFC were also generalizable to trauma-exposed AA women with or without PTSD in association with anxiety (
      • Mehta N.D.
      • Stevens J.S.
      • Li Z.
      • Fani N.
      • Gillespie C.F.
      • Ravi M.
      • et al.
      Inflammation, amygdala-ventromedial prefrontal functional connectivity and symptoms of anxiety and PTSD in African American women recruited from an inner-city hospital: Preliminary results.
      ), and to unmedicated bipolar patients (
      • Gong J.
      • Chen G.
      • Chen F.
      • Zhong S.
      • Chen P.
      • Zhong H.
      • et al.
      Association between resting-state functional connectivity of amygdala subregions and peripheral pro-inflammation cytokines levels in bipolar disorder.
      ).
      Complementary task-fMRI studies. Relationships between endogenous inflammatory markers and low rsFC with amygdala is supported by a recent report that an endotoxin-stimulated inflammatory factor associated with heighted amygdala activation to fear>happy faces, which in turn associated with symptoms of anxious arousal in depression (
      • Boukezzi S.
      • Costi S.
      • Shin L.M.
      • Kim-Schulze S.
      • Cathomas F.
      • Collins A.
      • et al.
      Exaggerated amygdala response to threat and association with immune hyperactivity in depression.
      ). Importantly, while not all studies report similar associations between inflammation and amygdala reactivity (
      • RJT Mocking
      • Nap T.S.
      • Westerink A.M.
      • Assies J.
      • Vaz F.M.
      • Koeter M.W.J.
      • et al.
      Biological profiling of prospective antidepressant response in major depressive disorder: Associations with (neuro)inflammation, fatty acid metabolism, and amygdala-reactivity.
      ), TNF-antagonism with infliximab in patients with inflammatory illness reduced depressive symptoms in association with decreased amygdala reactivity to emotional face-processing (
      • Davies K.A.
      • Cooper E.
      • Voon V.
      • Tibble J.
      • Cercignani M.
      • Harrison N.A.
      Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms.
      ). Savitz and colleagues also extended findings of relationships between inflammation and amygdala reactivity to a broader network of regions activated by inflammatory stimuli in concert with amygdala (Section 3b, Figure 1d) by showing positive correlations between inflammatory genes in peripheral blood immune cells and activation of amygdala, vmPFC, and hippocampus to sad>happy faces (
      • 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.
      ). Emotional task fMRI also revealed relationships between inflammatory cytokines (IL-1beta, IL2) and PFC, insula and/or ACC activation in women with a history of suicidality or depression (
      • Conejero I.
      • Jaussent I.
      • Cazals A.
      • Thouvenot E.
      • Mura T.
      • Le Bars E.
      • et al.
      Association between baseline pro-inflammatory cytokines and brain activation during social exclusion in patients with vulnerability to suicide and depressive disorder.
      ), and generally anti-inflammatory T regulatory cells inversely correlated with dorsolateral PFC activation in bipolar depression (
      • Poletti S.
      • de Wit H.
      • Mazza E.
      • Wijkhuijs A.J.M.
      • Locatelli C.
      • Aggio V.
      • et al.
      Th17 cells correlate positively to the structural and functional integrity of the brain in bipolar depression and healthy controls.
      ). Therefore, endogenous inflammation-associated increases in reactivity of amygdala, PFC and functionally-related regions like insula are consistent with effects of inflammatory stimuli on these regions, and may contribute to low amygdala-vmPFC rsFC seen in psychiatric patients.

      c Interoceptive, Default Mode, and other Large-Scale Networks

      Similar to findings that inflammation effects on the brain extend beyond individual regions/circuits (Section 2b), network analyses have revealed endogenous inflammation/rsFC associations within largescale networks in psychiatric patients that overlap with inflammation-sensitive regions/circuits constructed by meta-analysis (
      • Kraynak T.E.
      • Marsland A.L.
      • Wager T.D.
      • Gianaros P.J.
      Functional neuroanatomy of peripheral inflammatory physiology: A meta-analysis of human neuroimaging studies.
      ), e.g., DMN (
      • Sheline Y.I.
      • Barch D.M.
      • Price J.L.
      • Rundle M.M.
      • Vaishnavi S.N.
      • Snyder A.Z.
      • et al.
      The default mode network and self-referential processes in depression.
      ,
      • Hamilton J.P.
      • Farmer M.
      • Fogelman P.
      • Gotlib I.H.
      Depressive Rumination, the Default-Mode Network, and the Dark Matter of Clinical Neuroscience.
      ), ventral attention network (VAN)(
      • Seeley W.W.
      The Salience Network: A Neural System for Perceiving and Responding to Homeostatic Demands.
      ), and interoceptive pathways involving insula (
      • Savitz J.
      • Harrison N.A.
      Interoception and Inflammation in Psychiatric Disorders.
      ,
      • Barrett L.F.
      • Simmons W.K.
      Interoceptive predictions in the brain.
      ). In high CRP-depressed (>3mg/L, n=33/83) versus healthy controls (n=46), Aruldass et al. reported low rsFC within VAN (insular/frontal opercular cortex) and posterior cingulate cortex (PCC) of DMN, and many features of this predefined network negatively correlated with CRP, IL-6, and neutrophils in all patients (
      • Aruldass A.R.
      • Kitzbichler M.G.
      • Morgan S.E.
      • Lim S.
      • Lynall M.-E.
      • Turner L.
      • et al.
      Dysconnectivity of a brain functional network was associated with blood inflammatory markers in depression.
      ). While Kitzbichler et al. reported a greater proportion of negatively weighted rsFC features within DMN in depressed, particularly high CRP, patients in this same cohort along with positive correlations between CRP and proton density (PD; tissue-free water/edema) within DMN (
      • Kitzbichler M.G.
      • Aruldass A.R.
      • Barker G.J.
      • Wood T.C.
      • Dowell N.G.
      • Hurley S.A.
      • et al.
      Peripheral inflammation is associated with micro-structural and functional connectivity changes in depression-related brain networks.
      ), analysis of all 70,500 possible pair-wise correlations between individual edges and CRP in all patients also revealed positive associations primarily with hippocampus. However, positive correlations between CRP and PD in PCC subregions mediated negative relationships between CRP and PCC-mPFC rsFC, but not positive relationships between CRP and PCC-hippocampus rsFC. Thus, inflammation-related structural changes in key regions of high CRP patients may contribute to low within-network rsFC, subsequently influencing rsFC with outside networks/regions possibly not as directly impacted by inflammation. While exclusively negative CRP-rsFC associations found using a similar strategy with less parcellations (100 versus 376) in another depressed cohort (n=44)(
      • Yin L.
      • Xu X.
      • Chen G.
      • Mehta N.D.
      • Haroon E.
      • Miller A.H.
      • et al.
      Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.
      ) suggest that fine-grained, agnostic approaches may be necessary to reveal positive correlations. While stronger internetwork DMN-VAN rsFC was also seen in association with CRP in a small depression cohort (n=27)(
      • Beckmann F.E.
      • Seidenbecher S.
      • Metzger C.D.
      • Gescher D.M.
      • Carballedo A.
      • Tozzi L.
      • et al.
      C-reactive protein is related to a distinct set of alterations in resting-state functional connectivity contributing to a differential pathophysiology of major depressive disorder.
      ), negative seed-to-voxel rsFC correlations for insula and DMN were reported for IL-6 in unmedicated bipolar depressed and schizophrenic patients (
      • Chen P.
      • Chen F.
      • Chen G.
      • Zhong S.
      • Gong J.
      • Zhong H.
      • et al.
      Inflammation is associated with decreased functional connectivity of insula in unmedicated bipolar disorder.
      ,
      • King S.
      • Holleran L.
      • Mothersill D.
      • Patlola S.
      • Rokita K.
      • McManus R.
      • et al.
      Early life Adversity, functional connectivity and cognitive performance in Schizophrenia: The mediating role of IL-6.
      ). Thus, peripheral inflammation in psychiatric patients primarily associated with low connectivity within large-scale networks, with some evidence of increased connectivity across networks or with other brain regions.

      4. Conclusions and translational implications

      Herein, we discuss key findings from an emerging literature describing associations between inflammatory markers and functional dysconnectivity in both discrete circuits and broad networks relevant to transdiagnostic symptoms in depression and other disorders (Figure 2). Results are consistent with and described in the context of a wealth of data demonstrating the causal impact of clinically or experimentally administered cytokines or inflammatory stimuli on neurotransmitters and functional activity and connectivity in the same regions and circuits in association with relevant symptoms (Section 2/Figure 1). Supporting evidence of inflammation-associated alterations in neurotransmitters, task activation, structural connectivity, and edema in patients (Section 3/Table 1) further serve as potential mechanisms of functional dysconnectivity.
      Most studies reported relationships between low structural or functional connectivity and innate/inflammatory cytokines (ILs, TNF, IFNs assessed individually or as a composite) or CRP (thought to reflect activity of multiple cytokines). While a handful of studies measured more than one cytokine (but not CRP) and only reported on one marker (IL-1beta, IL-6, IL-8, TFN)(
      • Wang Y.
      • Wei Y.
      • Edmiston E.K.
      • Womer F.Y.
      • Zhang X.
      • Duan J.
      • et al.
      Altered structural connectivity and cytokine levels in Schizophrenia and Genetic high-risk individuals: Associations with disease states and vulnerability.
      ,
      • Rengasamy M.
      • Brundin L.
      • Griffo A.
      • Panny B.
      • Capan C.
      • Forton C.
      • et al.
      Cytokine and Reward Circuitry Relationships in Treatment-Resistant Depression.
      ,
      • Tang G.
      • Chen P.
      • Chen G.
      • Zhong S.
      • Gong J.
      • Zhong H.
      • et al.
      Inflammation is correlated with abnormal functional connectivity in unmedicated bipolar depression: an independent component analysis study of resting-state fMRI.
      ,
      • Sugimoto K.
      • Kakeda S.
      • Watanabe K.
      • Katsuki A.
      • Ueda I.
      • Igata N.
      • et al.
      Relationship between white matter integrity and serum inflammatory cytokine levels in drug-naive patients with major depressive disorder: diffusion tensor imaging study using tract-based spatial statistics.
      ,
      • Lim J.
      • Sohn H.
      • Kwon M.S.
      • Kim B.
      White Matter Alterations Associated with Pro-inflammatory Cytokines in Patients with Major Depressive Disorder.
      ,
      • Gong J.
      • Chen G.
      • Chen F.
      • Zhong S.
      • Chen P.
      • Zhong H.
      • et al.
      Association between resting-state functional connectivity of amygdala subregions and peripheral pro-inflammation cytokines levels in bipolar disorder.
      ,
      • Chen P.
      • Chen F.
      • Chen G.
      • Zhong S.
      • Gong J.
      • Zhong H.
      • et al.
      Inflammation is associated with decreased functional connectivity of insula in unmedicated bipolar disorder.
      ), it is not clear whether this represents biologically significant cytokine-circuit associations within the context of chronic low-grade inflammation in patients, or rather inter-study/marker variability in methods/detection. As this area of research expands, relationships between connectivity and individual immune markers can be examined in large datasets, and longitudinal and experimental studies can confirm stability, neurobiological mechanisms, and causal associations/pathway specificity.
      For example, in region/circuit analyses, relationships between inflammation and low rsFC in frontostriatal reward/motor-related circuits have as emerged as a consistent finding across laboratories and samples (Figure 2), and parallel findings on the impact of inflammatory stimuli on multimodal neuroimaging outcomes in these regions (Section 2)(
      • Bekhbat M.
      • Treadway M.T.
      • Felger J.C.
      Inflammation as a Pathophysiologic Pathway to Anhedonia: Mechanisms and Therapeutic Implications.
      ). Our recent report that levodopa increased VS-vmPFC rsFC only in depressed patients with higher CRP in association with improved anhedonia not only link inflammation-related reward circuit deficits to dopamine (
      • Bekhbat M.
      • Li Z.
      • Mehta N.D.
      • Treadway M.T.
      • Lucido M.J.
      • Woolwine B.J.
      • et al.
      Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study.
      )(Section 3a), but also indicate rsFC as a modifiable imaging biomarker for the efficacy of interventions to reverse the impact of inflammation on the brain. Future research using this approach in patients with high inflammation will focus on other targetable substrates, e.g., glutamate or immune-modulating therapies (
      • Drevets W.C.
      • Wittenberg G.M.
      • Bullmore E.T.
      • Manji H.K.
      Immune targets for therapeutic development in depression: towards precision medicine.
      ,
      • Bekhbat M.
      • Treadway M.T.
      • Felger J.C.
      Inflammation as a Pathophysiologic Pathway to Anhedonia: Mechanisms and Therapeutic Implications.
      ).
      In sum, a growing field describes reliable associations between endogenous innate-immune/inflammatory markers and structural/functional dysconnectivity in regions, circuits and networks known to be sensitive to inflammatory stimuli in association with transdiagnostic symptoms in psychiatric patients. Future work will examine specificity/causality of these associations and their potential use as brain biomarkers to develop therapies targeted to patients with high inflammation (

      Miller AH, Haroon E, Felger JC (2017): Therapeutic Implications of Brain-Immune Interactions: Treatment in Translation. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 42:334-359.

      ,
      • Drevets W.C.
      • Wittenberg G.M.
      • Bullmore E.T.
      • Manji H.K.
      Immune targets for therapeutic development in depression: towards precision medicine.
      ).

      Acknowledgements

      This work was supported by funds from the National Institute of Mental Health grants R01MH109637, R61MH121625 (JCF), K23MH114037 (DRG), F32MH119750 (MB), and F31MH119745 (NDM). Figure 2 artwork is credited to Katie Vicari: [email protected]; www.katierisvicari.com.
      Disclosures: Dr. Felger recently consulted for Cello Health BioConsulting on a topic unrelated to this work. All other authors report no biomedical financial interests or potential conflicts of interest.

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