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Peripheral Inflammation is Associated with Altered Substantia Nigra Activity and Psychomotor Slowing in Humans
Open accessAbstract
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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“typhoid vaccination has been associated with altered neural activity in the substantia nigra, a part of the basal ganglia that is involved in motor planning and reward seeking”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Brydon, Harrison, Walker, Steptoe, & Critchley, 2008
In the citing paper
“Brydon et al. (2008) examined Stroop performance after typhoid vaccination, and found that individuals with higher vaccine-induced IL-6 levels had significantly slower reaction times across both incongruent and congruent trials.”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Brydon et al., 2008
In the citing paper
“Thus, inflammation did not impair inhibitory control, but rather led to an overall psychomotor slowing and/or decrease in motivation (Brydon et al., 2008).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Brydon et al., 2008
In the citing paper
“Studies across the endotoxin, typhoid vaccination, and IFN-α paradigms have consistently shown that exogenous stimulation of proinflammatory cytokines leads to reports of increased fatigue (Brydon et al., 2008; Capuron et al., 2002; Dowell et al., 2016; Eisenberger et al., 2010a; Grigoleit et al., 2011; Harrison et al., 2009; Moieni et al., 2015) and decreases in ratings of vigor (Dowell et al., 2”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Brydon et al., 2008
In the citing paper
“Further, greater IL-6 following typhoid vaccination was associated with slower response times on all trials of a color-word Stroop task (both congruent and incongruent trials) (Brydon et al., 2008).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Brydon et al., 2008
In the citing paper
“Notably, increases in IL-6 and decreases in motor speed were both associated with altered activation patterns (enhanced activation) in the substantia nigra (Brydon et al., 2008).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Brydon et al., 2008
In the citing paper
“This is exemplified by typhoid vaccine studies which can lead to increases in fatigue within 2–3 hours despite eliciting only mild, acute increases in inflammation (Brydon et al., 2008).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Brydon et al., 2008
In the citing paper
“Mild, short-term increases in inflammation are sufficient to cause somatic symptoms, particularly fatigue.”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Brydon et al., 2008
In the citing paper
“depression and fatigue are the main side effects of treatment with IFN-α (111, 112).”
From Cytokine Research in Depression: Principles, Challenges, and Open Questions (2019) · cites this paper as [111]
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Li, Y., Jiang, Q., & Wang, L. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.777997 · Cited by 58
Khan, K., Najmi, A. K., & Akhtar, M. (2018) · Drug Research · doi:10.1055/a-0748-5518 · Cited by 55
“For example, normal volunteers injected with LPS exhibited acute increases in symptoms of depression and anxiety [54], and administration of a Salmonella typhi vaccine to healthy individuals produced depressed mood, fatigue, mental confusion, and psychomotor slowing [55].”
BackgroundByrne, M. L., Whittle, S., & Allen, N. B. (2016) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000311 · Cited by 55
“Glutamate concentrations (57,59) and metabolic activity (47) were also increased in the basal ganglia (especially striatal areas) in patients treated with cytokine injections, which, in turn, were associated with increased depressive symptoms, and activity in the substantia nigra was associated with peripheral inflamm…”
BackgroundInfluentialMacCormack, J. K., & Lindquist, K. A. (2016) · Emotion Review · doi:10.1177/1754073916639664 · Cited by 60
“negative mood (Brydon et al., 2008; Strike et al., 2004; Wright et al., 2005).”
Inflammation and dimensions of reward processing following exposure to the influenza vaccine
Boyle, C. C., Kuhlman, K. R., Dooley, L. N., Haydon, M. D., Robles, T. F., Ang, Y., Pizzagalli, D. A., & Bower, J. E. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.11.024 · Cited by 54
Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction
Baune, B. T., Camara, M.-L., Eyre, H. A., Jawahar, M. C., Anscomb, H., & Körner, H. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0027-8 · Cited by 50
“Increase in peripheral blood cytokine levels induced by lipopolysaccharide (LPS) or Salmonella typhi vaccination in healthy individuals caused symptoms of depression as well as fatigue, psychomotor slowing [106], and mental confusion [6] [107].”
Advancing precision psychiatry and targeted treatments: Insights from immunopsychiatry
Miller, A. H., Berk, M., Bloch, G., Briquet-Laugier, V., Brouillon, C., Cuthbert, B. N., Dantzer, R., Davis, M. C., Picker, L. D., Drevets, W. C., et al. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.01.002 · Cited by 55
Self-citationArnett, S., & Clark, I. A. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.04.004 · Cited by 49
“An effect of inflammatory mediators on the basal ganglia and cerebral cortex consistent with the behavioural changes seen in sickness behaviour has been noted by several authors, providing a mechanistic link between the described cytokine mediated changes in cellular neurophysiology and sickness behaviour (Brydon et a…”
BackgroundInteroception and Inflammation in Psychiatric Disorders
Savitz, J., & Harrison, N. A. (2018) · Biological Psychiatry: Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2017.12.011 · Cited by 126
“Slowing: Substantia Nigra Brydon, 2008 (88) 16 (WS) fMRI”
Self-citationTripathi, A., Bartosh, A., Whitehead, C., & Pillai, A. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02189-7 · Cited by 47
Inflaming the Brain: CRPS a Model Disease to Understand Neuroimmune Interactions in Chronic Pain
Linnman, C., Becerra, L. R., & Borsook, D. (2012) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9422-8 · Cited by 45
“We view this evidence, although not obtained in CRPS patients, as a potential overlapping mechanism: Typhoid vaccination (Brydon et al. 2008; Harrison et al. 2009a, b), endotoxin administration (Eisenberger et al. 2009, 2010; Inagaki et al. 2012; Kullmann et al. 2012), and psychological…”
Lifetime modulation of the pain system via neuroimmune and neuroendocrine interactions
Zouikr, I., & Karshikoff, B. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00276 · Cited by 45
“In several studies, the increased BOLD activity in these areas correlates with peripheral cytokine levels (210, 222, 226, 228, 229).”
BackgroundMarini, S., Berardis, D. D., Vellante, F., Santacroce, R., Orsolini, L., Valchera, A., Girinelli, G., Carano, A., Fornaro, M., Gambi, F., et al. (2016) · Mediators of Inflammation · doi:10.1155/2016/3476240 · Cited by 48
“Established correlations are that proinflammatory cytokines impair negative symptoms of schizophrenia [34, 35], deficiency in sustained attention [36], and psychomotor retardation [37].”
BackgroundGoldsmith, D. R., Bekhbat, M., Le, N., Chen, X., Woolwine, B. J., Li, Z., Haroon, E., & Felger, J. C. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.013 · Cited by 46
“Indeed, numerous studies in humans and laboratory animals have demonstrated that administration of inflammatory stimuli can impact dopamine release and affect the neural activation of key basal ganglia and prefrontal regions that subserve reward processing, motivation, and motor speed (Brydon et al., 2008; Capuron et…”
BackgroundSmith, A. P. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.09.002 · Cited by 44
“However, human studies using other paradigms (e.g. LPS challenge studies) support the view that central cytokines may be linked to sickness, mood alterations and psychomotor slowing in humans (Brydon et al., 2008; Harrison et al., 2009a,b; Mahoney and Ball, 2002; Vollmer-Conna et al., 2004).”
BackgroundKazemi, A., Noorbala, A. A., & Djafarian, K. (2019) · Journal of Human Nutrition and Dietetics · doi:10.1111/jhn.12675 · Cited by 44
Kautz, M. M., Coe, C. L., McArthur, B. A., Giollabhui, N. M., Ellman, L. M., Abramson, L. Y., & Alloy, L. B. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.02.029 · Cited by 42
“Upregulated inflammatory activity alters neural activity in several brain regions linked to depression, including anterior cingulate and insular cortex, and limbic circuitry (Brydon et al., 2008; Capuron et al., 2007; Capuron et al., 2012; Eisenberger et al., 2010; Harrison et al., 2009).”
BackgroundMechanisms associated with post-stroke depression and pharmacologic therapy
Zhan, Q., & Kong, F. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1274709 · Cited by 40
Can we vaccinate against depression?
Rook, G. A. W., Raison, C. L., & Lowry, C. A. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.03.018 · Cited by 39
Sharpley, A. L., Cooper, C. M., Williams, C., Godlewska, B. R., & Cowen, P. J. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4381-z · Cited by 39
“Previous research has shown that salmonella typhi (typhoid) vaccination stimulates a mild inflammatory response which results in increased levels of IL6, usually without causing significant morbidity (Brydon et al. 2008; Harrison et al. 2009a).”
Giollabhui, N. M., Slaney, C., Hemani, G., Foley, É. M., van der Most, P. J., Nolte, I. M., Snieder, H., Smith, G. D., Khandaker, G. M., & Hartman, C. A. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03372-w · Cited by 51
Autoimmunity, neuroinflammation, pathogen load: A decisive crosstalk in neuropsychiatric SLE
Jeltsch‐David, H., & Muller, S. (2016) · Journal of Autoimmunity · doi:10.1016/j.jaut.2016.04.005 · Cited by 40
“Then, LPS-administered healthy volunteers display acute anxiety and depressive behaviour and, as well, injection of a Salmonella typhi vaccine to healthy persons results in fatigue, depression, cognitive difficulty and psychomotor slowing [90,91].”
BackgroundSlaney, C., Sallis, H., Jones, H. J., Dardani, C., CHARGE Inflammation Working Group, Tilling, K. M., Munafo, M. R., Smith, G. D., Mahedy, L., & Khandaker, G. M. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.02.010 · Cited by 39
“All instruments had F-statistics > 10 (range:15.8 to 112.1), indicating adequate instrument strength (Table 3) (Burgess & Thompson, 2011; Staiger & Stock, 1997). re-running the analysis removing individuals with high CRP levels (>10 mg/l) did not substantially change the results, suggesting that…”
InfluentialSmith, R. S., Alkozei, A., Killgore, W. D. S., & Lane, R. D. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.09.011 · Cited by 39
“…nucleus accumbens, basal ganglia, and cerebellum) as well as levels of multiple neuromodulators, including dopamine, norepinephrine, and serotonin (Brydon et al., 2008; CamachoArroyo et al., 2009; Capuron et al., 2012, 2007, 2005; Eisenberger et al., 2010; Felger et al., 2016; Harrison et al.,…”
BackgroundThe impact of inflammation on neurocognition and risk for psychosis: a critical review
Kogan, S., Ospina, L. H., Mittal, V. A., & Kimhy, D. (2019) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-019-01073-2 · Cited by 38
“Cross-sectional studies have shown that IL-6 is associated with negative effects on cognition in healthy individuals [63, 64] and mild transient elevations of IL-6 induced in healthy adults are associated with negative performance on memory tests [65] and increased reaction time coupled with altered substantia nigra a…”
BackgroundThe inflammatory hypothesis of mood spectrum broadened to fibromyalgia and chronic fatigue syndrome.
Dell’Osso, L., Bazzichi, L. M., Baroni, S., Falaschi, V., Conversano, C., Carmassi, C., & Marazziti, D. (2015) · PubMed · Cited by 37
Brick by Brick: Building a Transdiagnostic Understanding of Inflammation in Psychiatry
Thylur, D. S., & Goldsmith, D. R. (2022) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000326 · Cited by 42
Glial mechanisms underlying major depressive disorder: Potential therapeutic opportunities
Rahman, S., & Alzarea, S. I. (2019) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2019.06.010 · Cited by 36
Peripheral and Central Glutamate Dyshomeostasis in Neurodegenerative Disorders
Onaolapo, A. Y., & Onaolapo, O. J. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666201015161919 · Cited by 37
Cytomegalovirus Antibody Elevation in Bipolar Disorder: Relation to Elevated Mood States
Prossin, A. R., Yolken, R. H., Kamali, M., Heitzeg, M. M., Kaplow, J. B., Coryell, W. H., & McInnis, M. G. (2015) · Neural Plasticity · doi:10.1155/2015/939780 · Cited by 36
“CMV IgG antibody concentrations were expressed quantitatively as both continuous (e.g., concentration) and dichotomous (e.g., seropositive, seronegative)measures, each derived via comparisons to standard samples run concurrently in each assay, as previously described [28].”
MethodBalter, L. J. T., Hulsken, S., Aldred, S., Drayson, M. T., Higgs, S., Zanten, J. V., Raymond, J. E., & Bosch, J. A. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.05.006 · Cited by 35
Longitudinal study of inflammatory markers and psychopathology in schizophrenia
Feng, T., McEvoy, J. P., & Miller, B. J. (2020) · Schizophrenia Research · doi:10.1016/j.schres.2020.10.003 · Cited by 35
Associations between dietary carotenoid intakes and the risk of depressive symptoms
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Clinical phenotypes of depressed patients with evidence of inflammation and somatic symptoms
Foley, É. M., Parkinson, J. T., Kappelmann, N., & Khandaker, G. M. (2021) · Comprehensive Psychoneuroendocrinology · doi:10.1016/j.cpnec.2021.100079 · Cited by 34
“In healthy volunteers, experimental immuno-activation was reported to alter activation of reward-related brain regions [5,22], including reduction in the ventral striatum responses to hedonic reward [7,14].”
Neuroimmune pathophysiology of long COVID
Moen, J. K., Baker, C. A., & Iwasaki, A. (2025) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13855 · Cited by 38
Saloner, R., Cherner, M., Grelotti, D. J., Paolillo, E. W., Moore, D. J., Heaton, R. K., Letendre, S. L., Kumar, A. M., Grant, I., & Ellis, R. J. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.09.012 · Cited by 32
“Although some conflicting evidence has been published, the preponderance of reports in humans support that inflammation downregulates multiple aspects of dopaminergic neurotransmission, including synthesis, packaging, and release of DA (Brydon et al., 2008; Capuron et al., 2012; Felger and Miller, 2012; Felger and Tre…”
BackgroundBekhbat, M., Goldsmith, D. R., Woolwine, B. J., Haroon, E., Miller, A. H., & Felger, J. C. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01258-z · Cited by 34
Zhao, Y., Liang, X., Zhu, F., Wen, Y. F., Xu, J., Yang, J., Ding, M., Cheng, B., Ma, M., Zhang, L., et al. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.10.005 · Cited by 31
“In addition, previous study found that cognitive processes, including reaction time and working memory, could be influenced by cytokines (Brydon et al., 2008).”
Miller, B. J., Herzig, K., Jokelainen, J. J., Karhu, T., Keinanen-Kiukaanniemi, S. M., Järvelin, M., Veijola, J. M., Viinamäki, H. T., Tanskanen, P., Jääskeläinen, E., et al. (2020) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-020-01134-x · Cited by 31
Short sleeping time and psychobiological responses to acute stress
Okamura, H., Tsuda, A., Yajima, J., Hamer, M., Horiuchi, S., Toyoshima, N., & Matsuishi, T. (2010) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2010.07.010 · Cited by 31
“In this study, the Stroop color word conflict task was selected as the mental stress test because this task is a very established stress task for assessing high-demand cognitive processing, including attention and executive control processes, via effects of stimulus conflict on psychomotor responses (Strike and Stepto…”
MethodDieset, I., Haukvik, U. K., Melle, I. S., Røssberg, J. I., Ueland, T., Hope, S., Dale, A. M., Djurovic, S., Aukrust, P., Agartz, I., et al. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.11.006 · Cited by 30
“…that peripheral inflammation is associated with increased metabolism in the basal ganglia causing symptoms often seen in schizophrenia, such as fatigue, anhedonia, loss of concentration and reduced energy (Capuron and Miller, 2011; Banks et al., 2002; Brydon et al., 2008; Eisenberger et al., 2010).”
BackgroundEneni, A.-E. O., Ben‐Azu, B., Ajayi, A. M., & Aderibigbe, A. O. (2023) · Journal of Molecular Neuroscience · doi:10.1007/s12031-022-02077-9 · Cited by 31
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
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 63
- Issue
- 11
- Pages
- 1022-1029
- ISSN
- 0006-3223 (ISSN-L)
- 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
- hybrid
- doi.org
- 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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