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Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GeorgiaNeuroscience Graduate Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, Georgia
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GeorgiaWinship Cancer Institute, Emory University, Atlanta, Georgia
Findings from numerous laboratories and across neuroimaging modalities have consistently shown that exogenous administration of cytokines or inflammatory stimuli that induce cytokines disrupts circuits and networks involved in motivation and motor activity, threat detection, anxiety, and 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 such as anhedonia and anxiety in psychiatric and at-risk populations. This review presents 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.
Inflammation in Psychiatric Disorders: Sources and Symptoms
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) (
). Many of these factors increase risk for both psychiatric and medical illnesses, suggesting shared pathophysiologic mechanisms that explain high rates of comorbidity (
). Activated innate immune cells release inflammatory cytokines, such as interleukins (ILs), tumor necrosis factor α (TNF), and interferons (IFNs), which then induce acute phase reactants such as C-reactive protein (CRP) from the liver. Numerous studies and meta-analyses report higher CRP and protein or gene expression markers of circulating inflammatory cytokines (e.g., IL-1, IL-6, TNF, IFNs) in depression as well as other psychiatric disorders sharing common symptom domains of reduced motivation, psychomotor slowing, and anxiety, including bipolar disorder, schizophrenia, anxiety disorders, and posttraumatic stress disorder (PTSD) (
). High peripheral inflammation, defined as CRP >3 mg/L (i.e., high risk for cardiometabolic disease), is observed, for example, in approximately 25% to 40% of depressed patients (
). Importantly, higher CRP and inflammatory cytokines have also been associated with resistance to conventional antidepressants in depression and worse clinical outcomes in schizophrenia (
Figure 1Sources and mechanisms of inflammation and its effects on neurotransmitters and circuits that contribute to psychiatric symptoms. (A) Mechanisms of innate immune activation and chronic low-grade inflammation. 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 such as 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. (B) Bidirectional inflammatory processes at the blood-brain interface. 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 blood-brain barrier, 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 such 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. (C) Inflammatory cytokines and associated oxidative molecules affect monoamine and glutamate neurotransmission. Inflammatory cytokines and the associated release of ROS and nitrogen species can impact neuronal function through several ways, including effects on neurotransmitters such as 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 phenylalanine to tyrosine and tyrosine to levodopa. 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 such as the D2 receptor. 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 such as QUIN (an NMDAR agonist) further increase glutamate signaling, including at extrasynaptic receptors, which leads to excitotoxicity and downstream generation of ROS (not shown). (D) 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. Neuroimaging of patients chronically treated with inflammatory cytokines (e.g., IFN-α) or healthy participants administered stimuli that induce cytokines (e.g., endotoxin, vaccination) has shown that cytokines affect reward- and motor-related regions and circuits as well as those involved in threat, anxiety, and emotional processing. For example, positron emission tomography and magnetic resonance spectroscopy studies in patients treated with IFN-α 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 and 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. 5-HTT, serotonin transporter; ACC, anterior cingulate cortex; BH4, tetrahydrobiopterin; CNS, central nervous system; CRP, C-reactive protein; DA, dopamine; dACC, dorsal ACC; 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; IL, interleukin; KYN, kynurenine; MAPK, mitogen-activated protein kinase; MAR, monoamine receptor; MAT, monoamine transporter; NE, norepinephrine; NFκB, nuclear factor kappa B; NLRP3, NOD- LRR- and pyrin domain-containing protein-3; NMDAR, NMDA receptor; PGE2, prostaglandin E2; QUIN, quinolinic acid; R, receptor; ROS, reactive oxygen species; SN, salience network; STAT, signal transducer and activator of transcription; TLR, toll-like receptor; TNF, tumor necrosis factor; Trp, tryptophan; VMAT2, vesicular monoamine transporter 2; vmPFC, ventromedial prefrontal cortex; VS, ventral striatum; xCT, cystine-glutamate exchanger.
Neuroinflammatory biomarkers in cerebrospinal fluid from 106 patients with recent-onset depression compared with 106 individually matched healthy control subjects.
), and postmortem studies show evidence of increased inflammatory cytokines and signaling pathways, activated microglia, and/or peripheral immune cell trafficking to brain parenchyma in depression, bipolar disorder, and schizophrenia (
A schizophrenia subgroup with elevated inflammation displays reduced microglia, increased peripheral immune cell and altered neurogenesis marker gene expression in the subependymal zone.
). However, lack of evidence of widespread blood-brain barrier (BBB) disruption (e.g., as indicated by CSF/circulating albumin, IgG ratios) observed in patients with depression versus control subjects (n = 106/group) or in relation to CRP (n = 73) (
Neuroinflammatory biomarkers in cerebrospinal fluid from 106 patients with recent-onset depression compared with 106 individually matched healthy control subjects.
) is consistent with evidence from animal models. For example, while monocyte trafficking and peripheral IL-6 are required for expression of anhedonic and depressive behaviors in chronic stress–induced depression models, the BBB remains relatively intact with region-specific decreases in integrity characterized by increased permeability to IL-6 in nucleus accumbens (NAc) (
). Reduced BBB proteins (e.g., claudin-5) were also seen in NAc of susceptible mice and postmortem NAc, but not prefrontal cortex (PFC) or hippocampus, of depressed patients (n = 39) (
While peripheral immune activation is sufficient to cause depressive symptoms (see below), it is important to note that this involves bidirectional processes whereby peripheral cytokines and immune cells interact with endothelial cells, astrocytes, and microglia to elaborate production of cytokines and inflammatory mediators; microglia in turn release chemokines that recruit peripheral cells (Figure 1B). These bidirectional mechanisms may be particularly relevant in disorders such as schizophrenia involving genetic, developmental, or autoimmune predispositions and inflammatory processes potentially initiating in the brain to engage the peripheral immune system (
Cerebrospinal fluid and blood biomarkers of neuroinflammation and blood-brain barrier in psychotic disorders and individually matched healthy controls.
Cerebrospinal fluid and blood biomarkers of neuroinflammation and blood-brain barrier in psychotic disorders and individually matched healthy controls.
). Conversely, TSPO (translocator protein) positron emission tomography (PET) imaging thought to reflect microglial/macrophage activation is often reported to be increased in depression (despite not correlating with peripheral inflammatory markers), but lower in schizophrenia (
Positron emission tomography studies of the glial cell marker translocator protein in patients with psychosis: A meta-analysis using individual participant data.
), rather than a reduced inflammatory state. Nevertheless, similar patterns of innate/inflammatory cytokines and acute phase reactants in blood and CSF of patients in relation to symptom domains across disorders reflect potential common mechanisms of the effects of innate immune activation on the brain (see below), regardless of its source.
Increased Inflammation and Transdiagnostic Symptoms: Cause-Effect Relationships
Inflammatory Cytokines Induce Symptoms of Reduced Motivation, Motor Slowing, and Anxiety
Consistent with the above-described role for inflammation in psychiatric disorders, a wealth of clinical and translational data demonstrate that administration of cytokines or inflammatory stimuli that induce cytokines affects neurotransmitters and circuits implicated in the pathophysiology of multiple disorders in association with symptoms of depression and anxiety (
) (Figure 1C, D). Some of the strongest clinical evidence of a potentially causal role for inflammation in psychiatric symptoms comes from patients chronically administered antiviral/antiproliferative cytokines such as IFN-α for infectious diseases/cancer (
). Up to 50% of patients treated with IFN-α reliably developed symptoms meeting criteria for major depression, and approximately 80% experienced fatigue, reduced energy, and/or psychomotor slowing (
Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: Association with fatigue, motor slowing, and increased evening cortisol.
). Acute administration of inflammatory stimuli, such as low-dose endotoxin/vaccination, which potently induces cytokines, transiently increases depressive/anxiety symptoms (
) in humans and laboratory animals and is used to study the impact of peripheral inflammation on the brain.
Endogenous Inflammation, Transdiagnostic Symptoms, and Reversal With Anticytokine Therapies
While inflammatory effects on relevant circuits and behaviors described above may represent adaptive responses promoting conservation of energy (e.g., reduced motivation/anhedonia, psychomotor slowing), heightened vigilance (e.g., threat detection, anxiety), or social/emotional adaptations during immune activation, chronically elevated inflammation may contribute to psychiatric symptoms (
). 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) (
), and numerous studies report high inflammation in schizophrenia in association with negative symptoms, including motivational deficits, blunted affect, and social withdrawal (
Association of inflammation with depression and anxiety: Evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts [published correction appears in Mol Psychiatry 2022; 27:1856].
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 patients with unipolar or bipolar depression who had evidence of increased inflammation (
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.
). These cause-effect relationships indicating that transdiagnostic symptoms such as 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 (
Impact of Inflammatory Stimuli on Brain Regions and Circuits: From the Clinic to the Laboratory
As described above, chronically administered inflammatory cytokine therapies such as 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 (
). These findings were subsequently linked to both low dopamine availability/release in caudate, putamen, and ventral striatum (VS) (including NAc) by PET (
) (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 such as 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 (
), seminal functional magnetic resonance imaging (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 connectivity (FC) and structural connectivity in psychiatric patients (see Structural and Functional Dysconnectivity in Patients With High Inflammation).
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 fMRI in subjects administered inflammatory cytokines (e.g., IFN-α therapy) or inflammatory stimuli (e.g., endotoxin or vaccination given in the laboratory) (
). 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 (
). Importantly, evidence from acute IFN-α or vaccine suggests that these neurotransmitter, structural, and functional changes in discrete regions known to regulate motivation and motor activity contribute more broadly to inflammation effects on FC in key circuits, including VS–ventromedial PFC (vmPFC), or as primary nodes within a global network that predicted depressive symptoms (
) 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 (
), 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 (
) 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, and dACC) in association with increased temporal variation of the rsFC signal only in amygdala, which in turn correlated with endotoxin-induced anxiety (
). 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 (
) and reinforce the importance of functionally connected regions involved in interoceptive/emotional processing and vigilance/threat detection to contribute to relevant symptoms induced by inflammation including anxiety.
Structural and Functional Dysconnectivity in Patients With High Inflammation
) (Figure 1D) and may contribute to disease pathophysiology and discrete symptoms in a subset of patients. While inflammation-associated structural and free water changes are reported in schizophrenia (
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 1Studies Assessing Relationships Between Endogenous Inflammation and Functional or Structural Neuroimaging Outcomes in the Context of Significant Psychiatric Symptoms or Diagnoses
Study
Population
Inflammatory Markers
Outcome
Brain Region/White Matter Tract
Resting-State Functional Connectivity and Supporting fMRI Studies
Circuits and Regions Relevant to Reduced Motivation or Psychomotor Slowing
Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.
Inflammation is correlated with abnormal functional connectivity in unmedicated bipolar depression: An independent component analysis study of resting-state fMRI [published online ahead of print Feb 19].
Increased inflammation and brain glutamate define a subtype of depression with decreased regional homogeneity, impaired network integrity, and anhedonia.
Inflammation negatively correlates with amygdala-ventromedial prefrontal functional connectivity in association with anxiety in patients with depression: Preliminary results.
Inflammation, amygdala-ventromedial prefrontal functional connectivity and symptoms of anxiety and PTSD in African American women recruited from an inner-city hospital: Preliminary results.
Inflammation and neurological disease-related genes are differentially expressed in depressed patients with mood disorders and correlate with morphometric and functional imaging abnormalities.
Biological profiling of prospective antidepressant response in major depressive disorder: Associations with (neuro)inflammation, fatty acid metabolism, and amygdala-reactivity.
Association between baseline pro-inflammatory cytokines and brain activation during social exclusion in patients with vulnerability to suicide and depressive disorder.
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.
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.
Altered structural connectivity and cytokine levels in schizophrenia and genetic high-risk individuals: Associations with disease states and vulnerability.
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 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 such as monocytes and T cells activate inflammatory signaling pathways and undergo metabolic reprogramming to facilitate the release of cytokines and cell trafficking to the brain. Inflammatory cytokines produced in the periphery and central nervous system can impact neural activation and functional connectivity within key brain regions, circuits, and networks relevant to psychiatric disorders through effects on neurotransmitters such as dopamine and glutamate or structural changes such as reduced white matter integrity. (Figure artwork is credited to Katie Vicari [www.katierisvicari.com]). BD, bipolar disorder; CRP, C-reactive protein; dACC, dorsal anterior cingulate cortex; DMN, default mode network; DS, dorsal striatum; IFN, interferon; IL, interleukin; Jak-Stat, Janus kinase/signal transducer and activator of transcription; MDD, major depressive disorder; NFκB, nuclear factor kappa B; NLRP3, NOD- LRR- and pyrin domain-containing protein-3; PD, proton density; pre-SMA, presupplementary motor area; PTSD, posttraumatic stress disorder; SZ, schizophrenia; TNF, tumor necrosis factor; TRD, treatment-resistant depression; VAN, ventral attention network; vmPFC, ventromedial prefrontal cortex; VS, ventral striatum.
Inflammation and Low rsFC in Nonpsychiatric Populations: Risk Factors Across the Life Span
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 nonpsychiatric populations. Consistent with the above-described effects of peripheral inflammation on regions and circuits involved in emotion regulation (see Impact of Inflammation on Regions and Circuits for Threat Detection, Anxiety, and Emotional and Interoceptive Processing), a composite index of CRP/inflammatory cytokines, or numbers of classical monocytes, was associated with low rsFC in an emotion regulation network in cohorts of at-risk African American youths (
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 (
), and an inflammatory cytokine composite was related to low salience, default mode network (DMN), and central executive internetwork rsFC in association with subclinical PTSD symptoms in stress-exposed firefighters (
). 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 (
). These findings, together with the impact of inflammatory stimuli on the brain (see Impact of Inflammatory Stimuli on Brain Regions and Circuits: From the Clinic to the Laboratory), 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 such as stress, early life adversity, and aging (
) and support these pathways as mechanisms of inflammation-related dysconnectivity in psychiatric patients.
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 (see Impact of Inflammation on Reward and Motor Regions and Circuits; Figure 1D), we and others 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 (
). For example, negative associations between plasma CRP and left VS-vmPFC rsFC were observed using both seed-to-voxelwise and targeted seed–to–region of interest 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 (
). 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 (
Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.
) for IL-6 in treatment-resistant depression and in our group for CRP in association with anhedonia in trauma-exposed inner-city African American women, while a composite of inflammatory cytokines and their receptors (
). 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 (
), 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 (
Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex.
), patients with bipolar disorder, including negative correlations between IL-8 and rsFC of right precentral gyrus within a somatomotor network, as demonstrated by Tang et al. (
Inflammation is correlated with abnormal functional connectivity in unmedicated bipolar depression: An independent component analysis study of resting-state fMRI [published online ahead of print Feb 19].
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). 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. 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 (
). These associations between inflammation and low activity or rsFC within frontostriatal circuits may involve its effects on neurotransmitters such as dopamine and glutamate (
) (Figure 1C, D). Plasma and CSF CRP in medically stable, unmedicated depressed patients was associated with left basal ganglia glutamate (using single-voxel MRS) (
), which jointly identified a larger network of low regional homogeneity (concordance of oscillatory activity in neighboring MRS voxels, including a reward-related subnetwork) (
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 (
Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: Evidence from a dopamine challenge study [published correction appears in Mol Psychiatry 2022; 27:4122].
). 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 (
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.
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 (
) (see Impact of Inflammatory Stimuli on Brain Regions and Circuits: From the Clinic to the Laboratory; 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 (
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 comorbid anxiety disorders or PTSD. Relationships between CRP or cytokines and rsFC between right amygdala and mPFC/vmPFC were also generalizable to trauma-exposed African American women with or without PTSD in association with anxiety (
Inflammation, amygdala-ventromedial prefrontal functional connectivity and symptoms of anxiety and PTSD in African American women recruited from an inner-city hospital: Preliminary results.
Relationships between endogenous inflammatory markers and low rsFC with amygdala are supported by a recent report that an endotoxin-stimulated inflammatory factor was associated with heightened amygdala activation to fear > happy faces, which in turn was associated with symptoms of anxious arousal in depression (
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 (
Inflammation and neurological disease-related genes are differentially expressed in depressed patients with mood disorders and correlate with morphometric and functional imaging abnormalities.
) also extended findings of relationships between inflammation and amygdala reactivity to a broader network of regions activated by inflammatory stimuli in concert with amygdala (see Impact of Inflammation on Regions and Circuits for Threat Detection, Anxiety, and Emotional and Interoceptive Processing; 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. Emotional task fMRI also revealed relationships between inflammatory cytokines (IL-1β, IL-2) and PFC, insula, and/or ACC activation in women with a history of suicidality or depression (
Association between baseline pro-inflammatory cytokines and brain activation during social exclusion in patients with vulnerability to suicide and depressive disorder.
). Therefore, endogenous inflammation-associated increases in reactivity of amygdala, PFC, and functionally related regions such as insula are consistent with effects of inflammatory stimuli on these regions and may contribute to low amygdala-vmPFC rsFC seen in psychiatric patients.
Interoceptive, Default Mode, and Other Large-Scale Networks
) reported low rsFC within ventral attention network (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. While Kitzbichler et al. (
) reported a greater proportion of negatively weighted rsFC features within DMN in depressed patients, particularly patients with high CRP, in this same cohort along with positive correlations between CRP and proton density (tissue–free water/edema) within DMN, analysis of all 70,500 possible pairwise correlations between individual edges and CRP in all patients also revealed positive associations primarily with hippocampus. However, positive correlations between CRP and proton density 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 patients with high CRP may contribute to low within-network rsFC, subsequently influencing rsFC with outside networks/regions possibly not as directly impacted by inflammation. Exclusively negative CRP-rsFC associations found using a similar strategy with less parcellations (100 vs. 376) in another depressed cohort (n = 44) (
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–ventral attention network rsFC was also seen in association with CRP in a small depression cohort (n = 27) (
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 patients with bipolar depression and in patients with schizophrenia (
). 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.
Conclusions and Translational Implications
Herein, we discussed 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 (see Impact of Inflammatory Stimuli on Brain Regions and Circuits: From the Clinic to the Laboratory; Figure 1). Inflammation-associated alterations in neurotransmitters, task activation, structural connectivity, and edema in patients (see Structural and Functional Dysconnectivity in Patients With High Inflammation; Table 1) further serve as potential mechanisms of functional dysconnectivity.
Most studies reported relationships between low structural connectivity or FC 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 reported on only one marker (IL-1β, IL-6, IL-8, TNF) (
Altered structural connectivity and cytokine levels in schizophrenia and genetic high-risk individuals: Associations with disease states and vulnerability.
Inflammation is correlated with abnormal functional connectivity in unmedicated bipolar depression: An independent component analysis study of resting-state fMRI [published online ahead of print Feb 19].
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.
), it is not clear whether this represents biologically significant cytokine-circuit associations within the context of chronic low-grade inflammation in patients or rather interstudy/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 emerged as a consistent finding across laboratories and samples (Figure 2), along with parallel findings on the impact of inflammatory stimuli on multimodal neuroimaging outcomes in these regions (see Impact of Inflammatory Stimuli on Brain Regions and Circuits: From the Clinic to the Laboratory) (
). Our recent report that levodopa increased VS-vmPFC rsFC only in depressed patients with higher CRP in association with improved anhedonia not only links inflammation-related reward circuit deficits to dopamine (
Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: Evidence from a dopamine challenge study [published correction appears in Mol Psychiatry 2022; 27:4122].
) (see Frontostriatal Circuits and Transdiagnostic Symptoms of Reduced Motivation and Psychomotor Slowing), but also indicates that rsFC is 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 (
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 (
This work was supported by the National Institute of Mental Health (Grant Nos. R01MH109637 and R61MH121625 [to JCF], Grant No. K23MH114037 [to DRG], Grant No. F32MH119750 [to MB], and Grant No. F31MH119745 [to NDM]).
JCF 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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