Enhanced Instructed Fear Learning in Delusion-Proneness

Abstract

Psychosis is associated with distorted perceptions and deficient bottom-up learning such as classical fear conditioning. This has been interpreted as reflecting imprecise priors in low-level predictive coding systems. Paradoxically, overly strong beliefs, such as overvalued beliefs and delusions, are also present in psychosis-associated states. In line with this, research has suggested that patients with psychosis and associated phenotypes rely more on high-order priors to interpret perceptual input. In this behavioural and fMRI study we studied two types of fear learning, i.e., instructed fear learning mediated by verbal suggestions about fear contingencies and classical fear conditioning mediated by low level associative learning, in delusion proneness-a trait in healthy individuals linked to psychotic disorders. Subjects were shown four faces out of which two were coupled with an aversive stimulation (CS+) while two were not (CS-) in a fear conditioning procedure. Before the conditioning, subjects were informed about the contingencies for two of the faces of each type, while no information was given for the two other faces. We could thereby study the effect of both classical fear conditioning and instructed fear learning. Our main outcome variable was evaluative rating of the faces. Simultaneously, fMRI-measurements were performed to study underlying mechanisms. We postulated that instructed fear learning, measured with evaluative ratings, is stronger in psychosis-related phenotypes, in contrast to classical fear conditioning that has repeatedly been shown to be weaker in these groups. In line with our hypothesis, we observed significantly larger instructed fear learning on a behavioural level in delusion-prone individuals (n = 20) compared to non-delusion-prone subjects (n = 23; n = 20 in fMRI study). Instructed fear learning was associated with a bilateral activation of lateral orbitofrontal cortex that did not differ significantly between groups. However, delusion-prone subjects showed a stronger functional connectivity between right lateral orbitofrontal cortex and regions processing fear and pain. Our results suggest that psychosis-related states are associated with a strong instructed fear learning in addition to previously reported weak classical fear conditioning. Given the similarity between nocebo paradigms and instructed fear learning, our results also have an impact on understanding why nocebo effects differ between individuals.

Keywords: classical fear conditioning; delusion-proneness; expectations; fMRI; instructed fear learning; nocebo effect; orbitofrontal cortex; priors.

FIGURE 1

Subjects and experimental design. (A) Timeline of paradigm. In the acquisition and extinction phases each CS was displayed 12 times for 5 s, and the jittered inter-trial interval was 11.5 ± 2 s. The CS+ were coupled with UCS (mildly painful electric stimulation) with a 50% contingency in the acquisition phase and there was no UCS in the extinction phase. Participants were asked to rate how friendly each CS was experienced, using a visual analogue scale (−100 to 100). In order to estimate learning we calculated the difference between CS- rating and CS+ rating for each CS-pair (instructed and non-instructed). This difference score is referred to as “affective learning index”’ and the main outcome value in the study. We analysed three affective learning indices: (1) T1: after instruction learning, (2) T2: after acquisition, and (3) T3: after extinction. All ratings were normalized in regards to T0. (B) In the instruction phase, two of the faces (instructed CS+ and CS-; iCS+/iCS-) were coupled with information about their contingencies with the UCS that included a fabricated short description about their personality and the risk of being associated with an aversive stimulation. The two other CS faces (non-instructed CS+ and CS-; niCS+/niCS-) contained no information about their contingencies with the UCS. Instructions were presented twice (followed by ratings–T1’ and T1) in order to increase the effect of information.

FIGURE 2

Behavioural results of instructed and non-instructed learning. (A) Timeline of likability ratings for instructed CS-stimuli over the three phases. (B) In line with our hypothesis the affective learning index was higher for the hDP (mean = 125.77, SD = 93.06) than for the lDP (mean = 74.50, SD = 67.98) for the instructed CS-stimuli and we found a significant group effect (p = 0.044) over all phases thus confirming our main hypothesis. (C) Timeline of likability ratings for non-instructed CS-stimuli over the three phrases. (D) For the non-instructed stimuli, there was no significant effect of group (p = 0.105). The average non-instructed affective learning index after acquisition was somewhat larger (albeit non-significant) in the delusion-prone group than in the control group (hDP: mean = 89.45, SD = 81.52; lDP: mean = 63.00, SD = 62.16). As suggested from the time-line the largest part of this non-significant difference was dependent on T3 (ratings after extinction). At phases T2 the affective learning index was significantly larger than 0 (p < 0.00001) for each group, indicating that the fear conditioning worked and the subjects learned the contingencies. Error bars: 2 S.E.

FIGURE 3

Relation between instruction effects and delusional distress. (A) Correlations between distress scores and overall instructed affective learning index (averaged over three phases) in hDP (r = 0.555, p = 0.011, Pearson correlation tests). (B) Correlations between normalised distress scores and overall instructed affective learning index (averaged over three phases) in hDP (r = 0.433, p = 0.056, Pearson correlation tests). (C) Rating of the explicit influence of instructions in lDP and hDP. The group difference is on the border of significance t = −1.910, p = 0.063, df = 40 (independent two-sample t-test). (D) Correlation between distress scores and explicit rating of instruction influence in hDP (r = 0.562, p = 0.010, Pearson correlation tests). (E) Correlation between normalised distress scores and explicit rating of instruction influence in in hDP (r = 0.491, p = 0.028, Pearson correlation tests). Error bars: 2 S.E.

FIGURE 4

Brain activity related to the effects of conditioning and instructions—BOLD response (A,B) and PPI analyses (C,D). (A) Main effect of fear (CS+ vs. CS-): an activation in caudal anterior cingulate cortex (cACC), bilateral anterior insula, premotor/dorsolateral prefrontal cortex (dlPFC), right temporo-parietal junction (rTPJ) was observed (Supplementary Table 1). The activation pattern was similar for instructed (iCS+ vs. iCS-) and non-instructed (niCS+ vs. niCS-) stimuli. No group difference was observed. (B) Main effect of instructions: bilateral activations in lateral orbitofrontal cortex (lOfc) (ROI analysis and whole brain analysis) and an activation in dlPFC (whole brain analysis) were observed (Supplementary Table 2). This effect was mainly driven by the hDP, and only this group showed significant activations in lOfc (bilateraly). (C) A psychophysiological interaction (PPI) analysis on the effect of instructions (vs. non-instructed trials): An increased connectivity between the right lOfc and functionally defined low-level pain processing areas (i.e., right posterior insula) (Z = 3.29, pFWE = 0.004) was observed specifically in hDP (i.e., compared to in lDP). (D) A PPI-analysis on the effects of instruction on fear processing: A larger connectivity between lOfc and the cACC (overlapping with fear related activation) was observed in hDP than in lDP (Z = 2.96, pFWE = 0.012). Error bars: S.E.

FIGURE 5

Relation between delusion-proneness and functional connectivity. The functional connectivity (PPI-analysis) between the right lOfc and i.e., right posterior insula ROI as an effect of instructions (vs. non-instructed trials) correlated with conviction scores in the hDP (Z = 3.44, pFWE = 0.003). A similar effect was shown for PDI-total scores (Z = 3.29, pFWE = 0.004) and normalised conviction scores also in the hDP (Z = 2.77, pFWE = 0.016).