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

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.