title: Neural basis of impaired safety signaling in Obsessive Compulsive Disorder.
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.
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom; aa545@cam.ac.uk.|Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, United Kingdom.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors.forename: Annemieke M
authors.initials: AM
authors.lastname: Apergis-Schoute
authors.affiliation: Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.|Department of Psychology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Claire M
authors.identifier: 0000-0001-9065-403X
authors.initials: CM
authors.lastname: Gillan
authors.affiliation: Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.|Hertfordshire Partnership University NHS Foundation Trust, University of Hertfordshire, Welwyn Garden City AL8 6HG, United Kingdom.|Postgraduate Medical School, University of Hertfordshire, Hatfield AL10 9AB, United Kingdom.
authors.forename: Naomi A
authors.initials: NA
authors.lastname: Fineberg
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, United Kingdom.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors.forename: Emilio
authors.initials: E
authors.lastname: Fernandez-Egea
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, United Kingdom.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Sahakian
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
mesh_terms: D000328:Adult; D000679:Amygdala / Q000378:metabolism; D001007:Anxiety; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D001931:Brain Mapping; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004553:Electric Conductivity; D005260:Female; D006801:Humans; D007858:Learning; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D009474:Neurons / Q000378:metabolism*; D009771:Obsessive-Compulsive Disorder / Q000000981:diagnostic imaging / Q000209:etiology* / Q000378:metabolism*; D015398:Signal Transduction; D012879:Skin Physiological Phenomena; D055815:Young Adult
keywords: Obsessive Compulsive Disorder; Pavlovian; fMRI; safety signals; vmPFC