Reduced safety processing during aversive social conditioning in psychosis and clinical risk

Abstract

Social impairment occurs across the psychosis spectrum, but its pathophysiology remains poorly understood. Here we tested the hypothesis that reduced differential responses (aversive vs. neutral) in neural circuitry underpinning aversive conditioning of social stimuli characterizes the psychosis spectrum. Participants age 10-30 included a healthy control group (HC, analyzed n = 36) and a psychosis spectrum group (PSY, n = 71), including 49 at clinical risk for psychosis and 22 with a frank psychotic disorder. 3T fMRI utilized a passive aversive conditioning paradigm, with neutral faces as conditioned stimuli (CS) and a scream as the unconditioned stimulus. fMRI conditioning was indexed as the activation difference between aversive and neutral trials. Analysis focused on amygdala, ventromedial prefrontal cortex, and anterior insula, regions previously implicated in aversive and social-emotional processing. Ventromedial prefrontal cortex activated more to neutral than aversive CS; this "safety effect" was driven by HC and reduced in PSY, and correlated with subjective emotional ratings following conditioning. Insula showed the expected aversive conditioning effect, and although no group differences were found, its activation in PSY correlated with anxiety severity. Unexpectedly, amygdala did not show aversive conditioning; its activation trended greater for neutral than aversive CS, and did not differ significantly based on group or symptom severity. We conclude that abnormalities in social aversive conditioning are present across the psychosis spectrum including clinical risk, linked to a failure of safety processing. Aversive and safety learning provide translational paradigms yielding insight into pathophysiology of psychosis risk, and providing potential targets for therapeutic and preventative interventions.

Fig. 1

Passive aversive delay conditioning fMRI paradigm. One neutral male face (CS+) co-terminated with an aversive scream US on half of the trials (CS+p) and was not paired with the scream on the other half (CS+u). The second neutral male face (CS−) was never paired with the scream

Fig. 2

Differential conditioning effects in CS+u > CS− contrast (all participants, n = 107). Hot colors represent CS+u > CS− activation, cold colors represent deactivation (CS− > CS+u). Significant clusters in vmPFC (a) and AIC (b) are corrected within the combined-ROI mask using threshold-free cluster enhancement (TFCE), p < 0.05; c shows the subthreshold trend in amygdala (peak TFCE p = 0.07)

Fig. 3

Differential conditioning effects (CS+ > CS− contrast) in vmPFC for two-group comparison (a) and three-group linear trend analysis (b). Voxelwise maps show significant TFCE-corrected clusters with greater differential activation in healthy controls (HC) than in the psychosis spectrum group (PSY) (42 voxels, peak t = −3.60 at MNI −4,58,−2); the clinical risk (CR) was intermediate between these two groups as shown by the significant linear trend (38 voxels, peak t = −3.63 at MNI −2,62,−10). The cold (blue) color indicates that the vmPFC deactivation is stronger (more negative) in HC than PSY. Descriptive bar graphs show data extracted from vmPFC; errors bars are SEM

Fig. 4

a Differential conditioning data extracted from the vmPFC ROI correlated significantly with differential post-conditioning subjective valence ratings (participants with valid behavioral data, n = 102). A more normative activation pattern in the vmPFC (negative values, stronger response to CS− than CS+) was associated with a more normative subjective rating pattern (negative values, CS− rated more positive than CS+). b Descriptive voxelwise image shows location of this correlation in vmPFC, display threshold z = 2.33. c Bar graphs show that HC subjectively rated CS− positively, while PSY did not