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Cited by 381Tryptophan and brain disordersNeuroinflammation and Neurodegeneration MechanismsStress Responses and Cortisol

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Peripheral Inflammation is Associated with Altered Substantia Nigra Activity and Psychomotor Slowing in Humans

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Brydon, Lena, Harrison, Neil A., Walker, Cicely, Steptoe, Andrew, Critchley, Hugo D.·2008·Biological Psychiatry
DOI 10.1016/j.biopsych.2007.12.007PMC PMC2885493
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Abstract

BackgroundSystemic infections commonly cause sickness symptoms including psychomotor retardation. Inflammatory cytokines released during the innate immune response are implicated in the communication of peripheral inflammatory signals to the brain.MethodsWe used functional magnetic resonance brain imaging (fMRI) to investigate neural effects of peripheral inflammation following typhoid vaccination in 16 healthy men, using a double-blind, randomized, crossover-controlled design.ResultsVaccination had no global effect on neurovascular coupling but markedly perturbed neural reactivity within substantia nigra during low-level visual stimulation. During a cognitive task, individuals in whom typhoid vaccination engendered higher levels of circulating interleukin-6 had significantly slower reaction time responses. Prolonged reaction times and larger interleukin-6 responses were associated with evoked neural activity within substantia nigra.ConclusionsOur findings provide mechanistic insights into the interaction between inflammation and neurocognitive performance, specifically implicating circulating cytokines and midbrain dopaminergic nuclei in mediating the psychomotor consequences of systemic infection. Systemic infections commonly cause sickness symptoms including psychomotor retardation. Inflammatory cytokines released during the innate immune response are implicated in the communication of peripheral inflammatory signals to the brain. We used functional magnetic resonance brain imaging (fMRI) to investigate neural effects of peripheral inflammation following typhoid vaccination in 16 healthy men, using a double-blind, randomized, crossover-controlled design. Vaccination had no global effect on neurovascular coupling but markedly perturbed neural reactivity within substantia nigra during low-level visual stimulation. During a cognitive task, individuals in whom typhoid vaccination engendered higher levels of circulating interleukin-6 had significantly slower reaction time responses. Prolonged reaction times and larger interleukin-6 responses were associated with evoked neural activity within substantia nigra. Our findings provide mechanistic insights into the interaction between inflammation and neurocognitive performance, specifically implicating circulating cytokines and midbrain dopaminergic nuclei in mediating the psychomotor consequences of systemic infection.

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Figures

Figure 1 High-contrast flashing checkerboard task used as a potent stimulus of primary visual cortical regions. Participants fixated on a cross at the center of the screen and pressed a key whenever the brightness of the cross changed.
Figure 1 High-contrast flashing checkerboard task used as a potent stimulus of primary visual cortical regions. Participants fixated on a cross at the center of the screen and pressed a key whenever the brightness of the cross changed.CC BY · PubMed Central
Figure 2 Cognitive color-word Stroop task. Participants pressed a key to select the response word that correctly identified the print color of the target word. Congruent and incongruent conditions were presented separately and examples of these are illustrated here. In the congruent example (upper panel), the correct response is green. In the incongruent example, requiring greater cognitive effort (lower panel), the correct response is red.
Figure 2 Cognitive color-word Stroop task. Participants pressed a key to select the response word that correctly identified the print color of the target word. Congruent and incongruent conditions were presented separately and examples of these are illustrated here. In the congruent example (upper panel), the correct response is green. In the incongruent example, requiring greater cognitive effort (lower panel), the correct response is red.CC BY · PubMed Central
Figure 3 Cytokine response to typhoid vaccination. A high-sensitivity, two-site ELISA was used to measure plasma concentrations of IL-6 in blood samples drawn at the beginning of each session (baseline) and 3 hours following intramuscular injection with either typhoid vaccine or normal saline placebo (postscan). Data are presented as the mean increase in picograms of IL-6 per milliliter of plasma ± SEM in vaccine (solid line) and placebo (dashed line) conditions (*p < .001, n = 16; significant treatment by sample interaction, F = 7.98, p = .013). ELISA, enzyme-linked immunosorbent assay; IL-6, interleukin-6.
Figure 3 Cytokine response to typhoid vaccination. A high-sensitivity, two-site ELISA was used to measure plasma concentrations of IL-6 in blood samples drawn at the beginning of each session (baseline) and 3 hours following intramuscular injection with either typhoid vaccine or normal saline placebo (postscan). Data are presented as the mean increase in picograms of IL-6 per milliliter of plasma ± SEM in vaccine (solid line) and placebo (dashed line) conditions (*p < .001, n = 16; significant treatment by sample interaction, F = 7.98, p = .013). ELISA, enzyme-linked immunosorbent assay; IL-6, interleukin-6.CC BY · PubMed Central
Figure 4 Effect of peripheral inflammation on neural reactivity during low-grade visual stimulation task. (A) Mean BOLD signal change (+SEM) during checkerboard stimulus in all voxels probabilistically assigned to Brodmann areas 17 and 18 for vaccine and placebo conditions. There was no significant interaction between mean activation to visual stimulation and inflammatory state in either BA17 (p = .11) or BA18 (p = .34), confirming no effect of inflammation on neurovascular coupling. (B) Interaction between task performance and inflammatory state shows a highly significant change in BOLD signal within the left substantia nigra during performance of flashing checkerboard task (p = .002 after whole brain family-wise error [FWE] correction at p = .05). BA, Brodmann area; BOLD, blood oxygenation level-dependent; FWE, family-wise error.
Figure 4 Effect of peripheral inflammation on neural reactivity during low-grade visual stimulation task. (A) Mean BOLD signal change (+SEM) during checkerboard stimulus in all voxels probabilistically assigned to Brodmann areas 17 and 18 for vaccine and placebo conditions. There was no significant interaction between mean activation to visual stimulation and inflammatory state in either BA17 (p = .11) or BA18 (p = .34), confirming no effect of inflammation on neurovascular coupling. (B) Interaction between task performance and inflammatory state shows a highly significant change in BOLD signal within the left substantia nigra during performance of flashing checkerboard task (p = .002 after whole brain family-wise error [FWE] correction at p = .05). BA, Brodmann area; BOLD, blood oxygenation level-dependent; FWE, family-wise error.CC BY · PubMed Central
Figure 5 Relationship between IL-6 response to typhoid vaccine and reaction time performance on Stroop task. Scatter plot illustrating the mean key press reaction time in milliseconds (congruent and incongruent conditions grouped) as a function of the mean plasma IL-6 response to typhoid vaccine (increase between baseline and 3 hours) (r = .82, p < .001). IL-6, interleukin-6.
Figure 5 Relationship between IL-6 response to typhoid vaccine and reaction time performance on Stroop task. Scatter plot illustrating the mean key press reaction time in milliseconds (congruent and incongruent conditions grouped) as a function of the mean plasma IL-6 response to typhoid vaccine (increase between baseline and 3 hours) (r = .82, p < .001). IL-6, interleukin-6.CC BY · PubMed Central
Figure 6 IL-6 response to typhoid vaccine predicts enhanced neural activation within left substantia nigra during Stroop task performance. (A) fMRI analysis revealed heightened BOLD activity within left substantia nigra during performance of the cognitive Stroop task in the vaccine condition (threshold p < .001, illustrated at p < .005 uncorrected). (B) Scatter plot illustrating the relationship between substantia nigra activity (BOLD response within an 8 mm region of interest centered on the peak voxel at MNI −12, −2, −8) and mean IL-6 response to typhoid vaccine (p = .005). BOLD, blood oxygenation level-dependent; fMRI, functional magnetic resonance imaging; IL-6, interleukin-6; MNI, Montreal Neurological Institute.
Figure 6 IL-6 response to typhoid vaccine predicts enhanced neural activation within left substantia nigra during Stroop task performance. (A) fMRI analysis revealed heightened BOLD activity within left substantia nigra during performance of the cognitive Stroop task in the vaccine condition (threshold p < .001, illustrated at p < .005 uncorrected). (B) Scatter plot illustrating the relationship between substantia nigra activity (BOLD response within an 8 mm region of interest centered on the peak voxel at MNI −12, −2, −8) and mean IL-6 response to typhoid vaccine (p = .005). BOLD, blood oxygenation level-dependent; fMRI, functional magnetic resonance imaging; IL-6, interleukin-6; MNI, Montreal Neurological Institute.CC BY · PubMed Central
Figure 7 Enhanced substantia nigra activity predicts reaction time slowing. Mean response time on the cognitive Stroop task was significantly correlated with neural activity in the same left substantia nigra region of interest. (A) Amplified image of BOLD response in left SN that covaried with reaction time in the vaccine condition. (B) Scatter plot illustrating the relationship between substantia nigra activity (BOLD response within an 8 mm region of interest centered on the peak voxel at MNI −12, −2, −8) and mean reaction time in typhoid vaccine condition (p = .03). BOLD, blood oxygenation level-dependent; MNI, Montreal Neurological Institute; SN, substantia nigra.
Figure 7 Enhanced substantia nigra activity predicts reaction time slowing. Mean response time on the cognitive Stroop task was significantly correlated with neural activity in the same left substantia nigra region of interest. (A) Amplified image of BOLD response in left SN that covaried with reaction time in the vaccine condition. (B) Scatter plot illustrating the relationship between substantia nigra activity (BOLD response within an 8 mm region of interest centered on the peak voxel at MNI −12, −2, −8) and mean reaction time in typhoid vaccine condition (p = .03). BOLD, blood oxygenation level-dependent; MNI, Montreal Neurological Institute; SN, substantia nigra.CC BY · PubMed Central

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Metadata

Authors
Brydon, L., Harrison, N. A., Walker, C., Steptoe, A., & Critchley, H. D.
Affiliations
  • UCL Queen Square Institute of Neurology (GB)
  • Wellcome Centre for Human Neuroimaging (GB)
  • Brighton and Sussex Medical School (GB)
Corresponding author
Brydon, Lena
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2008-06
Volume
63
Issue
11
Pages
1022-1029
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2007.12.007
PMC
PMC2885493
OpenAlex
W2059416963
Cited by
381
References
48
Citations by year
2026: 5 · 2025: 20 · 2024: 23 · 2023: 22 · 2022: 16 · 2021: 41 · 2020: 25 · 2019: 20 · 2018: 26 · 2017: 15 · 2016: 35 · 2015: 26 · 2014: 17 · 2013: 19 · 2012: 25
FWCI
5.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Sussex Research Online (University of Sussex) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
Funders
  • Wellcome Trust
  • British Heart Foundation
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
peripheral inflammation, substantia nigra, psychomotor retardation, typhoid vaccination, interleukin-6, sickness behavior, neuroinflammation, dopaminergic midbrain, reaction time, neurovascular coupling, systemic infection, cytokines
MeSH terms
Adolescent, Adult, Brain Mapping, Double-Blind Method, Humans, Image Processing, Computer-Assisted, Inflammation, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Oxygen, Photic Stimulation, Psychomotor Performance, Reaction Time, Substantia Nigra, Typhoid Fever, Vaccination, Interleukin-6, Cross-Over Studies, Motor Skills Disorders

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