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.

Keywords: Obsessive Compulsive Disorder; Pavlovian; fMRI; safety signals; vmPFC.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Threat reversal paradigm and learning as reflected by skin conductance measurements. (A) One of the faces coterminated with a shock to the right wrist on one-third of the trials (eight CS+ US trials, which were excluded from analyses) and was therefore associated (16 CS+ trials) whereas the other face was safe (16 CS– trials), and during reversal, these contingencies were reversed so that the old CS+ became the new CS– and vice versa with the same number of trials. (B) Measured SCRs demonstrated that both OCD patients and controls acquired early (t42 = 5.808, P = 0.0000007; t34 = 5.704, P = 0.000002) and late (t42 = 5.196, P = 0.000006; t34 = 6.630, P = 0.0000001) threat learning. A between-group repeated-measures analysis with two factors (acquisition and reversal) and two stages each (early and late) revealed an significant main effect of group overall reflecting stronger differential learning in controls (F1, 76 = 5.666, P = 0.02) but also a significant Group × Stage interaction (F1, 76 = 5.87, P = 0.018), driven by a stronger differentiation deficit in OCD patients during late acquisition (F1, 76 = 5.635, P = 0.02) and late reversal (F1, 76 = 5.129, P = 0.026) when the presence of safety signaling is required. Asterisks in figure denote level of significance (*P < 0.05; ***P < 0.0001). Images of faces used with permission from Paul Ekman, PhD/Paul Ekman, LLC.

Fig. 2.

vmPFC hyperactivation in OCD patients for CS+ > CS– reveals the absence of a safety signal exists from early learning and its level predicts the amount of generalization during reversal. (A) Sagittal view of the early vmPFC (–3, 26, –8) hyperactivation in OCD. (B) First eigenvariates were extracted for this vmPFC cluster (t76 = 7.35, P < 0.0001, FWE, 112 voxels) for all stages of learning, which showed persistence of vmPFC hyperactivation in OCD for the CS+ > CS– contrast. (C) Reversal CS– > acquisition CS– revealed a significant signal for CS– updating in controls’ vmPFC (-2, 26, -2) only (t76 = 5.01, P = 0.023, FWE, 16 voxels). (D) vmPFC hyperactivation predicted the level of generalization in OCD patients, a score based on CS+ versus CS– differentiation during reversal at a highly significant level (r = 0.668, n = 43, P = 0.000001). (E) A subgroup of OCD patients (14/43) with incorrect contingency beliefs showed higher early vmPFC hyperactivation (F1, 41 = 5.395, P = 0.025). Asterisks in figure denote level of significance (*P < 0.05; ***P < 0.0001).

Fig. S1.

Left insula and globus pallidus exhibit stronger differential activation during late reversal in healthy controls. During late reversal, when only controls were accurately differentiating between the CS+ and the CS–, controls exhibited significantly stronger CS+ > CS– differentiation than OCD patients in the left insula (–30, 23, 1; t76 = 6.55, P < 0.0001, FWE, 260 voxels) and the left globus pallidus (–12, 2, 1; t76 = 6.04, P < 0.0001, FWE, 34 voxels). Asterisks denote level of significance (***P < 0.0001).

Fig. S2.

vmPFC versus baseline extracted separately for the CS+ and CS– per stage for each group confirms an absence of vmPFC safety signaling in OCD. These results confirmed an absence of vmPFC CS– processing in OCD (Early Acq, t42 = 0.710, P = 0.481; Late Acq, t42 = 0.174, P = 0.862; Early Rev, t42 = 1.261, P = 0.214 ; Late Rev, t42 = 0.588, P = 0.56) compared with mostly significant vmPFC CS+ processing (Early Acq, t42 = 2.579, P = 0.013; Late Acq, t42 = 1.731, P = 0.091; Early Rev, t42 = 2.366, P = 0.023; Late Rev, t42 = 2.673, P = 0.011). In contrast, controls exhibited a maintained presence of highly significant vmPFC CS– signaling (Early Acq, t34 = 3.545, P = 0.001; Late Acq, t34 = 4.105, P = 0.000239; Early Rev, t34 = 3.696, P = 0.001; Late Rev, t34 = 4.034, P = 0.000294) versus weak vmPFC CS+ signaling that was only marginally significant during early acquisition (Early Acq, t34 = 2.055, P = 0.048; Late Acq, t34 = 1.73, P = 0.092; Early Rev, t34 = 1.144, P = 0.261; Late Rev, t34 = 1.251, P = 0.22). Asterisks in figure denote level of significance (*P < 0.05; **P < 0.005; ***P < 0.0005).

Fig. 3.

OCD patients show increased early learning-related coupling of the vmPFC with salience areas. (A) Areas involved in salience processing showed increased coupling with the vmPFC during early conditioning in OCD patients. (B) First eigenvariates of these salience network regions depict significant increased coupling with the vmPFC in OCD patients during early acquisition dACC (–6, 17, 31; t76 = 6.81, P < 0.0001, FWE, 393 voxels), left insula (–33, 20, 7; t76 = 7.47, P < 0.0001, FWE, 506 voxels), right insula (42, 23, 4; t76 = 9.04, P < 0.0001, FWE, 549 voxels), and right thalamus (12, 2, 4; t76 = 6.29, P < 0.0001, FWE, 56 voxels).

Fig. S3.

Amygdala and caudate ROI eigenvariates during acquisition and reversal. (A) First eigenvariates from the left amygdala (–24, –1, –17) ROI showed comparable differential activation (CS+ > CS–) in OCD patients and controls during acquisition and reversal (F1, 76 < 0.4, P > 0.5). (B) Eigenvariates from the left caudate (–8, 2, 10) ROI demonstrated that differential signaling was present for both groups during learning (F1, 76 < 2.6, P > 0.1) but that only controls benefitted from differential striatal signaling during early (F1, 76 = 17.782, P < 0.0001) and late (F1, 76 = 26.372, P < 0.0001) reversal. Asterisks denote level of significance (***P < 0.0001).

Fig. S4.

Visualization of demographic and clinical characteristics of OCD patients and matched healthy controls.