Salience and central executive networks track overgeneralization of conditioned-fear in post-traumatic stress disorder

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Background Generalization of conditioned-fear, a core feature of post-traumatic stress disorder (PTSD), has been the focus of several recent neuroimaging studies. A striking outcome of these studies is the frequency with which neural correlates of generalization fall within hubs of well-established functional networks including salience (SN), central executive (CEN), and default networks (DN). Neural substrates of generalization found to date may thus reflect traces of large-scale brain networks that form more expansive neural representations of generalization. The present study includes the first network-based analysis of generalization and PTSD-related abnormalities therein. Methods fMRI responses in established intrinsic connectivity networks (ICNs) representing SN, CEN, and DN were assessed during a generalized conditioned-fear task in male combat veterans (N = 58) with wide-ranging PTSD symptom severity. The task included five rings of graded size. Extreme sizes served as conditioned danger-cues (CS+: paired with shock) and safety-cues (CS-), and the three intermediate sizes served as generalization stimuli (GSs) forming a continuum-of-size between CS+ and CS-. Generalization-gradients were assessed as behavioral and ICN response slopes from CS+, through GSs, to CS-. Increasing PTSD symptomatology was predicted to relate to less-steep slopes indicative of stronger generalization. Results SN, CEN, and DN responses fell along generalization-gradients with levels of generalization within and between SN and CEN scaling with PTSD symptom severity. Conclusions Neural substrates of generalized conditioned-fear include large-scale networks that adhere to the functional organization of the brain. Current findings implicate levels of generalization in SN and CEN as promising neural markers of PTSD.

Original languageEnglish (US)
Pages (from-to)2610-2619
Number of pages10
JournalPsychological medicine
Issue number15
Early online dateMay 5 2020
StatePublished - Nov 5 2021

Bibliographical note

Funding Information:
This research was made possible through an NIMH R00 grant (MH080130) to Dr Lissek, and by the Congressionally Directed Medical Research Program and the Department of Defense grant (PT074550) to Dr Sponheim.

Publisher Copyright:
© 2020 The Author(s). Published by Cambridge University Press.


  • Central executive network
  • conditioned-fear
  • default network
  • generalization
  • post-traumatic stress disorder
  • salience network

PubMed: MeSH publication types

  • Comparative Study
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.


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