Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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 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 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 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 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 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 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.