title: Circuit-wide structural and functional measures predict ventromedial prefrontal cortex fear generalization: implications for generalized anxiety disorder.
abstract: The ventromedial prefrontal cortex (vmPFC) plays a critical role in a number of evaluative processes, including risk assessment. Impaired discrimination between threat and safety is considered a hallmark of clinical anxiety. Here, we investigated the circuit-wide structural and functional mechanisms underlying vmPFC threat-safety assessment in humans. We tested patients with generalized anxiety disorder (GAD; n = 32, female) and healthy controls (n = 25, age-matched female) on a task that assessed the generalization of conditioned threat during fMRI scanning. The task consisted of seven rectangles of graded widths presented on a screen; only the midsize one was paired with mild electric shock [conditioned stimulus (CS)], while the others, safety cues, systematically varied in width by ±20, 40, and 60% [generalization stimuli (GS)] compared with the CS. We derived an index reflecting vmPFC functioning from the BOLD reactivity on a continuum of threat (CS) to safety (GS least similar to CS); patients with GAD showed less discrimination between threat and safety cues, compared with healthy controls (Greenberg et al., 2013b). Using structural, functional (i.e., resting-state), and diffusion MRI, we measured vmPFC thickness, vmPFC functional connectivity, and vmPFC structural connectivity within the corticolimbic systems. The results demonstrate that all three factors predict individual variability of vmPFC threat assessment in an independent fashion. Moreover, these neural features are also linked to GAD, most likely via an vmPFC fear generalization. Our results strongly suggest that vmPFC threat processing is closely associated with broader corticolimbic circuit anomalies, which may synergistically contribute to clinical anxiety.
authors.affiliation: Program in Neuroscience, Department of Psychology, and Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794, Department of Psychology, Northern Michigan University, Marquette, Michigan 49855, and Department of Radiology, A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129.
authors.forename: Jiook
authors.initials: J
authors.lastname: Cha
authors.forename: Tsafrir
authors.initials: T
authors.lastname: Greenberg
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dedora
authors.forename: Greg
authors.initials: G
authors.lastname: Hajcak
authors.forename: Lilianne R
authors.initials: LR
authors.lastname: Mujica-Parodi
mesh_terms: D000293:Adolescent; D000328:Adult; D001008:Anxiety Disorders / Q000473:pathology* / Q000503:physiopathology*; D001931:Brain Mapping; D003213:Conditioning, Psychological / Q000502:physiology; D056324:Diffusion Tensor Imaging; D005239:Fear / Q000502:physiology*; D005260:Female; D005793:Generalization, Psychological / Q000502:physiology; D006801:Humans; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008959:Models, Neurological; D015999:Multivariate Analysis; D017397:Prefrontal Cortex / Q000033:anatomy & histology* / Q000166:cytology*; D055815:Young Adult
keywords: anxiety; connectivity; fear conditioning; fear generalizaton; resting-state; tractography