Neural basis of impaired safety signaling in Obsessive Compulsive Disorder

Annemieke M. Apergis-Schoute, Claire M. Gillan, Emilio Fernandez-Egea, Naomi Fineberg, Barbara J. Sahakian, Trevor W. Robbins

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)


The ability to assign safety to stimuli in the environment is integral to everyday functioning. A key brain region for this evaluation is the ventromedial prefrontal cortex (vmPFC). To investigate the importance of vmPFC safety signaling, we used neuroimaging of Pavlovian fear reversal, a paradigm that involves flexible updating when the contingencies for a threatening (CS+) and safe (CS-) stimulus reverse, in a prototypical disorder of inflexible behavior influenced by anxiety, Obsessive Compulsive Disorder (OCD). Skin conductance responses in OCD patients (n = 43) failed to differentiate during reversal compared with healthy controls (n = 35), although significant differentiation did occur during early conditioning and amygdala BOLD signaling was unaffected in these patients. Increased vmPFC activation (for CS+ > CS-) during early conditioning predicted the degree of generalization in OCD patients during reversal, whereas vmPFC safety signals were absent throughout learning in these patients. Regions of the salience network (dorsal anterior cingulate, insula, and thalamus) showed early learning task-related hyperconnectivity with the vmPFC in OCD, consistent with biased processing of the CS+. Our findings reveal an absence of vmPFC safety signaling in OCD, undermining flexible threat updating and explicit contingency knowledge. Although differential threat learning can occur to some extent in the absence of vmPFC safety signals, effective CS- signaling becomes crucial during conflicting threat and safety cues. These results promote further investigation of vmPFC safety signaling in other anxiety disorders, with potential implications for the development of exposure-based therapies, in which safety signaling is likely to play a key role.

Original languageEnglish
Pages (from-to)3216-3221
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
Early online date6 Mar 2017
Publication statusPublished - 21 Mar 2017


  • FMRI
  • Obsessive Compulsive Disorder
  • Pavlovian
  • Safety signals
  • VmPFC


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