Neural Origins of Human Sickness in Interoceptive Responses to Inflammation

Abstract

BackgroundInflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking.MethodsIn a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning.ResultsTyphoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions.ConclusionsThese findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states.

Stress-induced brain activity, brain atrophy, and clinical disability in multiple sclerosis

“…These analyses revealed a significant link between fatigue and EDSS-related activity (t = −2.38; P = 0.021) and activity related to the FSS pyramidal scale (t = −2.50; P = 0.017) and thus supported the relevance of the findings in ref. 30. However, contrary to the findings in ref.…”

“…Findings made in an fMRI study investigating neural foundations of so-called "sickness behavior" in healthy subjects (30) may help explain the functional link between insular activity and disability in MS. Specifically, sickness behavior denotes a group of symptoms observed during the course of systemic infections including fatigue, depression, reduced exploratory behaviors, fever, and impaired cognitive performance (e.g., ref.…”

“…In ref. 30, either a typhoid vaccination or placebo was applied on one of two measurement days. Subsequently, inflammation, self-report variables (including fatigue), and cognitive performance were measured in an fMRI Stroop task.…”

Inflammation and the Silent Sequelae of Stroke

“…Second, Fig. 1 There is overlap between poststroke depression (PSD) and poststroke fatigue (PSF); most patients with PSD have PSF, but not all patients with PSF have PSD the perception of fatigue is common among otherwise healthy individuals who suffer infectious illnesses [47,48]. And, as with depression, the administration of proinflammatory cytokines [e.g., interleukin (IL)-6] is associated with the perception of fatigue [49].…”

“…The FAS has been validated in healthy cohorts [71]. FAS scores of 10-21 indicate that the patient is "not tired", scores of 22-34 indicate that the patient is "tired", and scores of [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] indicate that the patient is "very tired" [72]. We evaluated the relationship between the biomarkers of inflammation shown in Fig.…”