title: Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study.
abstract: Recent research on classical fear-conditioning in the anxiety disorders has identified overgeneralization of conditioned fear as an important conditioning correlate of anxiety pathology. Unfortunately, only one human neuroimaging study of classically conditioned fear generalization has been conducted, and the neural substrates of this clinically germane process remain largely unknown. The current generalization study employs a clinically validated generalization gradient paradigm, modified for the fMRI environment, to identify neural substrates of classically conditioned generalization that may function aberrantly in clinical anxiety. Stimuli include five rings of gradually increasing size with extreme sizes serving as cues of conditioned danger (CS+) and safety (CS-). The three intermediately sized rings serve as generalization stimuli (GSs) and create a continuum-of-size from CS+ to CS-. Results demonstrate 'positive' generalization gradients, reflected by declines in responding as the presented stimulus differentiates from CS+, in bilateral anterior insula, dorsomedial prefrontal cortex, and bilateral inferior parietal lobule. Conversely, 'negative' gradients, reflected by inclines in responding as the presented stimulus differentiates from CS+ were instantiated in bilateral ventral hippocampus, ventromedial prefrontal cortex and precuneus cortex. These results as well as those from connectivity analyses are discussed in relation to a working neurobiology of conditioned generalization centered on the hippocampus.
authors.affiliation: Mood and Anxiety Disorders Program, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD, USA, Department of Psychology, University of Minnesota-Twin Cities, MN, USA, Department of Psychology, University Wisconsin-Madison, Madison, WI, USA, and Laureate Institute for Brain Research, Tulsa, OK, USAMood and Anxiety Disorders Program, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD, USA, Department of Psychology, University of Minnesota-Twin Cities, MN, USA, Department of Psychology, University Wisconsin-Madison, Madison, WI, USA, and Laureate Institute for Brain Research, Tulsa, OK, USA smlissek@umn.edu.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Lissek
authors.affiliation: Mood and Anxiety Disorders Program, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD, USA, Department of Psychology, University of Minnesota-Twin Cities, MN, USA, Department of Psychology, University Wisconsin-Madison, Madison, WI, USA, and Laureate Institute for Brain Research, Tulsa, OK, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Bradford
authors.affiliation: Mood and Anxiety Disorders Program, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD, USA, Department of Psychology, University of Minnesota-Twin Cities, MN, USA, Department of Psychology, University Wisconsin-Madison, Madison, WI, USA, and Laureate Institute for Brain Research, Tulsa, OK, USA.
authors.forename: Ruben P
authors.initials: RP
authors.lastname: Alvarez
authors.affiliation: Mood and Anxiety Disorders Program, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD, USA, Department of Psychology, University of Minnesota-Twin Cities, MN, USA, Department of Psychology, University Wisconsin-Madison, Madison, WI, USA, and Laureate Institute for Brain Research, Tulsa, OK, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Burton
authors.affiliation: Mood and Anxiety Disorders Program, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD, USA, Department of Psychology, University of Minnesota-Twin Cities, MN, USA, Department of Psychology, University Wisconsin-Madison, Madison, WI, USA, and Laureate Institute for Brain Research, Tulsa, OK, USA.
authors.forename: Tori
authors.initials: T
authors.lastname: Espensen-Sturges
authors.affiliation: Mood and Anxiety Disorders Program, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD, USA, Department of Psychology, University of Minnesota-Twin Cities, MN, USA, Department of Psychology, University Wisconsin-Madison, Madison, WI, USA, and Laureate Institute for Brain Research, Tulsa, OK, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Reynolds
authors.affiliation: Mood and Anxiety Disorders Program, National Institute of Mental Health, Intramural Research Program, NIH, DHHS, Bethesda, MD, USA, Department of Psychology, University of Minnesota-Twin Cities, MN, USA, Department of Psychology, University Wisconsin-Madison, Madison, WI, USA, and Laureate Institute for Brain Research, Tulsa, OK, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Grillon
mesh_terms: D001921:Brain / Q000502:physiology*; D001931:Brain Mapping; D003214:Conditioning, Classical / Q000502:physiology*; D004597:Electroshock; D005239:Fear / Q000502:physiology*; D005260:Female; D005793:Generalization, Psychological / Q000502:physiology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways; D010775:Photic Stimulation; D055815:Young Adult
keywords: anxiety; conditioned generalization; fMRI; fear-conditioning; neurobiology