title: Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder.
abstract: Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala-calcarine (P=0.01) and amygdala-thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala-ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.
authors.affiliation: Mid-Atlantic Mental Illness Research Education and Clinical Center, Durham VA Medical Center, Durham, NC, USA.|Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.|Duke-UNC Brain Imaging and Analysis Center, Duke University, Durham, NC, USA.|Department of Psychology and Neuroscience, Center for Cognitive Neuroscience, Duke University, Durham, NC, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Morey
authors.affiliation: Department of Psychology, New York University, New York, NY, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Dunsmoor
authors.affiliation: Mid-Atlantic Mental Illness Research Education and Clinical Center, Durham VA Medical Center, Durham, NC, USA.|Duke-UNC Brain Imaging and Analysis Center, Duke University, Durham, NC, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Haswell
authors.affiliation: Department of Psychology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.|Virginia Tech-Carilion Research Institute, Virginia Polytechnic Institute and State University, Roanoke, VA, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Brown
authors.affiliation: School of Management, University of Iowa, Iowa City, IA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Vora
authors.affiliation: Mid-Atlantic Mental Illness Research Education and Clinical Center, Durham VA Medical Center, Durham, NC, USA.|Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Weiner
authors.affiliation: Department of Psychology and Neuroscience, Center for Cognitive Neuroscience, Duke University, Durham, NC, USA.
authors.forename: D
authors.initials: D
authors.lastname: Stjepanovic
authors.affiliation: Mid-Atlantic Mental Illness Research Education and Clinical Center, Durham VA Medical Center, Durham, NC, USA.|Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Wagner
authors.affiliation: Duke-UNC Brain Imaging and Analysis Center, Duke University, Durham, NC, USA.|Department of Psychology and Neuroscience, Center for Cognitive Neuroscience, Duke University, Durham, NC, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: LaBar
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology; D001931:Brain Mapping / Q000379:methods; D003213:Conditioning, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology* / Q000523:psychology*; D005260:Female; D005793:Generalization, Psychological / Q000502:physiology*; D006801:Humans; D007858:Learning / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D013313:Stress Disorders, Post-Traumatic / Q000503:physiopathology* / Q000523:psychology*; D014481:United States; D014728:Veterans / Q000523:psychology / Q000706:statistics & numerical data