title: Towards understanding sex differences in visceral pain: enhanced reactivation of classically-conditioned fear in healthy women.
abstract: Sex differences in learned fear regarding aversive gastrointestinal stimuli could play a role in the female preponderance of chronic abdominal pain. In a fear conditioning model with rectal pain as unconditioned stimulus (US), we compared healthy males and females with respect to neural responses during aversive visceral learning, extinction and re-activation of fear memory (i.e., reinstatement). To do so, conditioned visual stimuli (CS(+)) were consistently paired with painful rectal distensions as US, while different visual stimuli (CS(-)) were presented without US. During extinction, both CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, sexes were compared with respect to conditioned anticipatory neural activation (CS(+)>CS(-)). The results revealed that in late acquisition, CS+ presentation induced significantly greater anticipatory activation of the insula in women. During extinction, women demonstrated reduced activation of the posterior cingulate cortex. During reinstatement, the CS(+) led to greater activation of the hippocampus, thalamus and cerebellum in women. These group effects in neural activation during learning and memory processes were not accounted for by sex differences in pain thresholds, pain ratings, or stress parameters. In conclusion, this is the first study to support sex differences in neural processes mediating aversive visceral learning. Our finding of enhanced neural responses during reinstatement in key brain areas relevant for memory suggests enhanced reactivation of old fear memory trace in women. Sex differences in "gut memories" could play a role in the female preponderance of chronic abdominal pain.
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45147 Essen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Benson
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45147 Essen, Germany.
authors.forename: Joswin
authors.initials: J
authors.lastname: Kattoor
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45147 Essen, Germany; Institute of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45147 Essen, Germany.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Kullmann
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45147 Essen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hofmann
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45147 Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Engler
authors.affiliation: Institute of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45147 Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Forsting
authors.affiliation: Clinic for Neuroradiology, Innsbruck Medical University, Innrain 52, A-6020 Innsbruck, Austria.
authors.forename: Elke R
authors.initials: ER
authors.lastname: Gizewski
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45147 Essen, Germany. Electronic address: sigrid.elsenbruch@uk-essen.de.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Elsenbruch
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D003214:Conditioning, Classical / Q000502:physiology; D005239:Fear / Q000502:physiology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D012737:Sex Factors; D059265:Visceral Pain / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D006854:Hydrocortisone
keywords: Brain imaging; Emotional memory; Fear conditioning; Sex differences; Visceral pain