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

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.

Interleukin-6 Covaries Inversely with Hippocampal Grey Matter Volume in Middle-Aged Adults

“…In this regard, an important future direction will be to apply diffusion tensor imaging methods in examining the impact of inflammatory processes on brain networks implicated in cognitive decline. Finally, there is recent evidence that acute peripheral inflammation, as induced by typhoid vaccination, slows reaction times to cognitive processing tasks and affects corresponding changes in functional neural activation (45). These findings further highlight the potential influence of peripheral inflammation not only on structural neural pathways, but also on functional neural pathways supporting neurocognitive functions.…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…More recent studies have used functional magnetic resonance imaging (fMRI) to further characterize the effects of inflammatory stimuli on the basal ganglia. The data indicate that administration of inflammatory cytokines (ie, IFN-α) or inducers of the inflammatory response (eg, typhoid vaccination or endotoxin) lead to decreased neural activity in basal ganglia nuclei, specifically the ventral striatum (nucleus accumbens), in response to reward anticipation or feedback (Brydon et al, 2008;Harrison et al, 2015a, b;Eisenberger et al, 2010a;Capuron et al, 2012;Dowell et al, 2015). Studies have also indicated that not only is neural activity reduced in response to these reward-based tasks, but also there is an increased response to aversive stimuli (ie, loss) (Harrison et al, 2015b).…”

“…The reduced ventral striatal response to both IFN-α and endotoxin were correlated with depressive symptoms including anhedonia and fatigue as well as acute alterations in striatal microstructure as assessed by quantitative magnetization transfer (qMT) imaging (Eisenberger et al, 2010a;Capuron et al, 2012;Dowell et al, 2015). Of note, administration of typhoid vaccination has also been associated with alterations in neural activity in the substantia nigra (another basal ganglia nuclei) that was correlated with IL-6 and psychomotor slowing (Brydon et al, 2008). Taken together, these data indicate that using a host of neuroimaging paradigms, administration of a variety of inflammatory stimuli lead to consistent changes in brain regions responsible for motivation and motor activity.…”

“…Studies using IFN-α, typhoid vaccination, and endotoxin in humans have all identified motivational circuits and symptoms of anhedonia as being primary targets of inflammatory stimuli on the brain and behavior (Brydon et al, 2008;Harrison et al, 2009aHarrison et al, , b, 2015aEisenberger et al, 2010a;Capuron et al, 2012;Dowell et al, 2015). In addition, studies in patients with depression have also indicated strong relationships between peripheral inflammatory markers (eg, CRP) and changes in reward circuitry as well as alterations in glutamate metabolism in the basal ganglia, both of which were associated with symptoms of anhedonia Felger et al, 2016).…”

“…Another symptom domain closely related to the effects of inflammation on ventral striatal circuits are those that relate to dorsal striatal circuits. More specifically, objective and clinical signs and symptoms related to psychomotor speed have been associated with exposure to inflammatory stimuli and increased inflammatory markers in psychiatric disorders such as depression (Brydon et al, 2008;Majer et al, 2008;. Moreover, psychomotor retardation as measured by the Hamilton Depression Rating Scale (HAMD) was a symptom that was found to be especially responsive to cytokine antagonism in treatment-resistant depressed patients with high inflammation (Raison et al, 2013b).…”