title: A neural mediator of human anxiety sensitivity.
abstract: Advances in the neuroscientific understanding of bodily autonomic awareness, or interoception, have led to the hypothesis that human trait anxiety sensitivity (AS)-the fear of bodily autonomic arousal-is primarily mediated by the anterior insular cortex. Despite broad appeal, few experimental studies have comprehensively addressed this hypothesis. We recruited 55 individuals exhibiting a range of AS and assessed them with functional magnetic resonance imaging (fMRI) during aversive fear conditioning. For each participant, three primary measures of interest were derived: a trait Anxiety Sensitivity Index score; an in-scanner rating of elevated bodily anxiety sensations during fear conditioning; and a corresponding estimate of whole-brain functional activation to the conditioned versus nonconditioned stimuli. Using a voxel-wise mediation analysis framework, we formally tested for 'neural mediators' of the predicted association between trait AS score and in-scanner anxiety sensations during fear conditioning. Contrary to the anterior insular hypothesis, no evidence of significant mediation was observed for this brain region, which was instead linked to perceived anxiety sensations independently from AS. Evidence for significant mediation was obtained for the dorsal anterior cingulate cortex-a finding that we argue is more consistent with the hypothesized role of human cingulofrontal cortex in conscious threat appraisal processes, including threat-overestimation. This study offers an important neurobiological validation of the AS construct and identifies a specific neural substrate that may underlie high AS clinical phenotypes, including but not limited to panic disorder.
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Victoria, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Harrison
authors.affiliation: Institute of Neuropsychiatry and Addictions, Hospital Del Mar, CIBERSAM G21, Barcelona, Spain.|Department of Psychiatry, Autonomous University of Barcelona, Barcelona, Spain.|Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Miquel A
authors.initials: MA
authors.lastname: Fullana
authors.affiliation: Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona, Spain.|Department of Psychobiology and Methodology of Health Sciences, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Soriano-Mas
authors.affiliation: Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Via
authors.affiliation: MRI Research Unit, CRC Mar, Hospital Del Mar, CIBERSAM G21, Barcelona, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Pujol
authors.affiliation: Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Martínez-Zalacaín
authors.affiliation: Department of Psychiatry, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Daniella
authors.initials: D
authors.lastname: Tinoco-Gonzalez
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Victoria, Australia.|Orygen Youth Health Research Centre, Centre for Youth Mental Health, The University of Melbourne, Victoria, Australia.
authors.forename: Christopher G
authors.identifier: http://orcid.org/0000-0003-1431-3852
authors.initials: CG
authors.lastname: Davey
authors.affiliation: Department of Psychology and Neuroscience., University of Colorado, Colorado.
authors.forename: Marina
authors.initials: M
authors.lastname: López-Solà
authors.affiliation: Institute of Neuropsychiatry and Addictions, Hospital Del Mar, CIBERSAM G21, Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Pérez Sola
authors.affiliation: Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Menchón
authors.affiliation: Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona, Spain.
authors.forename: Narcís
authors.initials: N
authors.lastname: Cardoner
mesh_terms: D000293:Adolescent; D000328:Adult; D001007:Anxiety / Q000503:physiopathology*; D001341:Autonomic Nervous System / Q000503:physiopathology; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000503:physiopathology; D003213:Conditioning, Psychological; D005239:Fear; D005260:Female; D006179:Gyrus Cinguli / Q000503:physiopathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D055815:Young Adult
keywords: anxiety sensitivity; autonomic; cingulate cortex; fear; insular cortex; interoception