title: Human hippocampus arbitrates approach-avoidance conflict.
abstract: Animal models of human anxiety often invoke a conflict between approach and avoidance. In these, a key behavioral assay comprises passive avoidance of potential threat and inhibition, both thought to be controlled by ventral hippocampus. Efforts to translate these approaches to clinical contexts are hampered by the fact that it is not known whether humans manifest analogous approach-avoidance dispositions and, if so, whether they share a homologous neurobiological substrate. Here, we developed a paradigm to investigate the role of human hippocampus in arbitrating an approach-avoidance conflict under varying levels of potential threat. Across four experiments, subjects showed analogous behavior by adapting both passive avoidance behavior and behavioral inhibition to threat level. Using functional magnetic resonance imaging (fMRI), we observe that threat level engages the anterior hippocampus, the human homolog of rodent ventral hippocampus. Testing patients with selective hippocampal lesions, we demonstrate a causal role for the hippocampus with patients showing reduced passive avoidance behavior and inhibition across all threat levels. Our data provide the first human assay for approach-avoidance conflict akin to that of animal anxiety models. The findings bridge rodent and human research on passive avoidance and behavioral inhibition and furnish a framework for addressing the neuronal underpinnings of human anxiety disorders, where our data indicate a major role for the hippocampus.
authors.affiliation: Wellcome Trust Centre for Neuroimaging, University College London, London WC1N 3BG, UK; Berlin School of Mind and Brain, Humboldt University Berlin, 10099 Berlin, Germany; Psychiatric Hospital, University of Zurich, 8032 Zurich, Switzerland. Electronic address: dominik.bach@uzh.ch.
authors.forename: Dominik R
authors.initials: DR
authors.lastname: Bach
authors.affiliation: Wellcome Trust Centre for Neuroimaging, University College London, London WC1N 3BG, UK; Age Research Center, Karolinska Institute, 17111 Stockholm, Sweden.
authors.forename: Marc
authors.initials: M
authors.lastname: Guitart-Masip
authors.affiliation: Cognition and Brain Plasticity Unit, Institute of Biomedicine Research of Bellvitge (IDIBELL), 08908 Barcelona, Spain.
authors.forename: Pau A
authors.initials: PA
authors.lastname: Packard
authors.affiliation: Cognition and Brain Plasticity Unit, Institute of Biomedicine Research of Bellvitge (IDIBELL), 08908 Barcelona, Spain; Epilepsy Unit, University Hospital of Bellvitge, 08907 Barcelona, Spain.
authors.forename: Júlia
authors.initials: J
authors.lastname: Miró
authors.affiliation: Epilepsy Unit, University Hospital of Bellvitge, 08907 Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Falip
authors.affiliation: Cognition and Brain Plasticity Unit, Institute of Biomedicine Research of Bellvitge (IDIBELL), 08908 Barcelona, Spain; Department of Basic Psychology, University of Barcelona, 08007 Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Fuentemilla
authors.affiliation: Wellcome Trust Centre for Neuroimaging, University College London, London WC1N 3BG, UK; Berlin School of Mind and Brain, Humboldt University Berlin, 10099 Berlin, Germany.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Dolan
mesh_terms: D000328:Adult; D001362:Avoidance Learning / Q000502:physiology; D003220:Conflict, Psychological; D003674:Defense Mechanisms; D005260:Female; D006624:Hippocampus / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D033281:Nontherapeutic Human Experimentation; D018910:Video Games