title: Neural Substrates of Overgeneralized Conditioned Fear in PTSD.
abstract: OBJECTIVE
  Heightened generalization of fear from an aversively reinforced conditioned stimulus (CS+, a conditioned danger cue) to resembling stimuli is widely accepted as a pathogenic marker of posttraumatic stress disorder (PTSD). Indeed, a distress response to benign stimuli that "resemble" aspects of the trauma is a central feature of the disorder. To date, the link between overgeneralization of conditioned fear and PTSD derives largely from clinical observations, with limited empirical work on the subject. This represents the first effort to examine behavioral and brain indices of generalized conditioned fear in PTSD using systematic methods developed in animals known as generalization gradients: the gradual decline in conditioned responding as the presented stimulus gradually differentiates from CS+.
  
  
  METHODS
  Gradients of conditioned fear generalization were assessed using functional MRI and behavioral measures in U.S. combat veterans who served in Iraq or Afghanistan and had PTSD (N=26), subthreshold PTSD (N=19), or no PTSD (referred to as trauma control subjects) (N=17). Presented stimuli included rings of graded size, with extreme sizes serving as CS+ (paired with shock) and as a nonreinforced conditioned stimulus (CS-, a conditioned safety cue), and with intermediate sizes forming a continuum of similarity between CS+ and CS-. Generalization gradients were assessed as response slopes from CS+, through intermediate ring sizes, to CS-, with less steep slopes indicative of stronger generalization.
  
  
  RESULTS
  Relative to trauma control subjects, PTSD patients showed stronger conditioned generalization, as evidenced by less steep generalization gradients in both behavioral risk ratings and brain responses in the left and right anterior insula, left ventral hippocampus, dorsolateral and dorsomedial prefrontal cortex, and caudate nucleus. Severity of PTSD symptoms across the three study groups was positively correlated with levels of generalization at two such loci: the right anterior insula and left ventral hippocampus.
  
  
  CONCLUSIONS
  The results point to evidence of brain-based markers of overgeneralized fear conditioning related to PTSD. These findings provide further understanding of a central yet understudied symptom of trauma-related psychopathology.
authors: From the Department of Psychology, the Department of Psychiatry, and the Office of the College of Liberal Arts Associate Dean for Research, University of Minnesota, Minneapolis; the Department of Psychiatry, University of Pennsylvania, Philadelphia; and the Minneapolis VA Health Care System, Minneapolis.
authors: Antonia N
authors: AN
authors: Kaczkurkin
authors: From the Department of Psychology, the Department of Psychiatry, and the Office of the College of Liberal Arts Associate Dean for Research, University of Minnesota, Minneapolis; the Department of Psychiatry, University of Pennsylvania, Philadelphia; and the Minneapolis VA Health Care System, Minneapolis.
authors: Philip C
authors: PC
authors: Burton
authors: From the Department of Psychology, the Department of Psychiatry, and the Office of the College of Liberal Arts Associate Dean for Research, University of Minnesota, Minneapolis; the Department of Psychiatry, University of Pennsylvania, Philadelphia; and the Minneapolis VA Health Care System, Minneapolis.
authors: Shai M
authors: SM
authors: Chazin
authors: From the Department of Psychology, the Department of Psychiatry, and the Office of the College of Liberal Arts Associate Dean for Research, University of Minnesota, Minneapolis; the Department of Psychiatry, University of Pennsylvania, Philadelphia; and the Minneapolis VA Health Care System, Minneapolis.
authors: Adrienne B
authors: AB
authors: Manbeck
authors: From the Department of Psychology, the Department of Psychiatry, and the Office of the College of Liberal Arts Associate Dean for Research, University of Minnesota, Minneapolis; the Department of Psychiatry, University of Pennsylvania, Philadelphia; and the Minneapolis VA Health Care System, Minneapolis.
authors: Tori
authors: T
authors: Espensen-Sturges
authors: From the Department of Psychology, the Department of Psychiatry, and the Office of the College of Liberal Arts Associate Dean for Research, University of Minnesota, Minneapolis; the Department of Psychiatry, University of Pennsylvania, Philadelphia; and the Minneapolis VA Health Care System, Minneapolis.
authors: Samuel E
authors: SE
authors: Cooper
authors: From the Department of Psychology, the Department of Psychiatry, and the Office of the College of Liberal Arts Associate Dean for Research, University of Minnesota, Minneapolis; the Department of Psychiatry, University of Pennsylvania, Philadelphia; and the Minneapolis VA Health Care System, Minneapolis.
authors: Scott R
authors: SR
authors: Sponheim
authors: From the Department of Psychology, the Department of Psychiatry, and the Office of the College of Liberal Arts Associate Dean for Research, University of Minnesota, Minneapolis; the Department of Psychiatry, University of Pennsylvania, Philadelphia; and the Minneapolis VA Health Care System, Minneapolis.
authors: Shmuel
authors: S
authors: Lissek
mesh_terms: D000328:Adult; D055826:Afghan Campaign 2001-; D001143:Arousal / Q000502:physiology; D001921:Brain / Q000503:physiopathology; D001931:Brain Mapping; D003130:Combat Disorders / Q000175:diagnosis / Q000503:physiopathology* / Q000523:psychology; D003214:Conditioning, Classical / Q000502:physiology*; D004292:Dominance, Cerebral / Q000502:physiology; D005239:Fear / Q000502:physiology*; D005795:Generalization, Stimulus / Q000502:physiology*; D006801:Humans; D054542:Iraq War, 2003-2011; D008279:Magnetic Resonance Imaging; D008297:Male; D013313:Stress Disorders, Post-Traumatic / Q000175:diagnosis / Q000503:physiopathology* / Q000523:psychology; D014728:Veterans / Q000523:psychology*
keywords: Biological Markers; Cognitive Neuroscience; Emotion; Posttraumatic Stress Disorder