title: Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation.
abstract: Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double-blind randomized controlled experiment, 52 healthy volunteers were injected with 0.6ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2h 45min. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non-significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response.
authors.affiliation: Stress Research Institute, Stockholm University, Stockholm, Sweden; Osher Center for Integrative Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Division of Psychology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Mats.Lekander@ki.se.
authors.forename: Mats
authors.initials: M
authors.lastname: Lekander
authors.affiliation: Stress Research Institute, Stockholm University, Stockholm, Sweden; Osher Center for Integrative Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Division of Psychology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bianka
authors.initials: B
authors.lastname: Karshikoff
authors.affiliation: Division of Psychology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Emilia
authors.initials: E
authors.lastname: Johansson
authors.affiliation: Department of Anaesthesiology and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anne
authors.initials: A
authors.lastname: Soop
authors.affiliation: Osher Center for Integrative Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Fransson
authors.affiliation: Division of Psychology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Monell Chemical Senses Center, Philadelphia, PA, United States; Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Johan N
authors.initials: JN
authors.lastname: Lundström
authors.affiliation: Stress Research Institute, Stockholm University, Stockholm, Sweden; Osher Center for Integrative Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Division of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Andreasson
authors.affiliation: Osher Center for Integrative Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingvar
authors.affiliation: Osher Center for Integrative Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Predrag
authors.initials: P
authors.lastname: Petrovic
authors.affiliation: Stress Research Institute, Stockholm University, Stockholm, Sweden; Osher Center for Integrative Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Division of Psychology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Axelsson
authors.affiliation: Stress Research Institute, Stockholm University, Stockholm, Sweden; Osher Center for Integrative Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gustav
authors.initials: G
authors.lastname: Nilsonne
mesh_terms: D000328:Adult; D001416:Back Pain / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000503:physiopathology*; D063132:Connectome; D004311:Double-Blind Method; D005260:Female; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000503:physiopathology; D006261:Headache / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D055809:Illness Behavior; D007249:Inflammation / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D008297:Male; D009325:Nausea / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology; D055815:Young Adult
chemical_list: D008070:Lipopolysaccharides
keywords: Endotoxin; Inflammation; Insular cortex; Interoception; Intrinsic connectivity; Lipopolysaccharide; Resting state; Sickness behavior; Spontaneous pain; fMRI