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Research Article

Neural basis of impaired safety signaling in Obsessive Compulsive Disorder

Annemieke M. Apergis-Schoute, View ORCID ProfileClaire M. Gillan, Naomi A. Fineberg, Emilio Fernandez-Egea, Barbara J. Sahakian, and Trevor W. Robbins
PNAS first published March 6, 2017; https://doi.org/10.1073/pnas.1609194114
Annemieke M. Apergis-Schoute
aDepartment of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom;
bDepartment of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, United Kingdom;
cBehavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom;
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  • For correspondence: aa545@cam.ac.uk
Claire M. Gillan
cBehavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom;
dDepartment of Psychology, Trinity College Dublin, Dublin 2, Ireland;
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  • ORCID record for Claire M. Gillan
Naomi A. Fineberg
cBehavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom;
eHertfordshire Partnership University NHS Foundation Trust, University of Hertfordshire, Welwyn Garden City AL8 6HG, United Kingdom;
fPostgraduate Medical School, University of Hertfordshire, Hatfield AL10 9AB, United Kingdom
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Emilio Fernandez-Egea
bDepartment of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, United Kingdom;
cBehavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom;
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Barbara J. Sahakian
bDepartment of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, United Kingdom;
cBehavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom;
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Trevor W. Robbins
aDepartment of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom;
cBehavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom;
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  1. Edited by Ahmad R. Hariri, Duke University, Durham, NC and accepted by Editorial Board Member Marlene Behrmann December 19, 2016 (received for review July 27, 2016)

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Significance

Assigning safety to stimuli and situations forms an important part of everyday functioning. Obsessive Compulsive Disorder (OCD) is a prototypical disorder of inflexible behavior influenced by anxiety. Here we show, using neuroimaging of fear reversal learning, which involves a previously threatening stimulus becoming safe while a previously safe stimulus becomes threatening, that OCD patients fail to differentiate a safe from a threatening stimulus only after such a reversal, as measured by skin conductance responses. This OCD impairment in safety signaling, a likely prominent component of successful exposure therapy, is predicted and mediated by altered activity in a neural salience network including the ventromedial prefrontal cortex.

Abstract

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.

  • Obsessive Compulsive Disorder
  • vmPFC
  • Pavlovian
  • fMRI
  • safety signals

Footnotes

  • ↵1To whom correspondence should be addressed. Email: aa545{at}cam.ac.uk.
  • Author contributions: A.M.A.-S. and T.W.R. designed research; A.M.A.-S. and C.M.G. performed research; N.A.F. and E.F.-E. handled patient recruitment; A.M.A.-S. analyzed data; and A.M.A.-S., B.J.S., and T.W.R. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. A.R.H. is a Guest Editor invited by the Editorial Board.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1609194114/-/DCSupplemental.

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Neural basis of impaired safety signaling in OCD
Annemieke M. Apergis-Schoute, Claire M. Gillan, Naomi A. Fineberg, Emilio Fernandez-Egea, Barbara J. Sahakian, Trevor W. Robbins
Proceedings of the National Academy of Sciences Mar 2017, 201609194; DOI: 10.1073/pnas.1609194114

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Neural basis of impaired safety signaling in OCD
Annemieke M. Apergis-Schoute, Claire M. Gillan, Naomi A. Fineberg, Emilio Fernandez-Egea, Barbara J. Sahakian, Trevor W. Robbins
Proceedings of the National Academy of Sciences Mar 2017, 201609194; DOI: 10.1073/pnas.1609194114
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