52. Abnormal Anterior Insula Activity During Fear Generalization in Schizophrenia

Abstract

Abstract Background: Generalization from previous experiences allows us to evaluate the affective value of novel events. A breakdown of this fundamental ability may lead to incorrect attributions of affective value that could give rise to psychotic symptoms. To examine this hypothesis, we tested whether the generalization of conditioned fear responses is abnormal in schizophrenia, using functional magnetic resonance imaging (fMRI). Methods: 37 schizophrenia and 32 healthy subjects, matched for age, and sex, underwent an fMRI scan while participating in a Pavlovian fear conditioning and generalization paradigm. During the conditioning phase, one face was used as a conditioned stimulus and paired with an electrical shock (the CS+), whereas a different face was used as a neutral stimulus that was never paired with a shock (the CS−). In the generalization phase, five stimuli that were different morphs between the CS+ to the CS- were selected based on each individual’s ability to discriminate the two faces. Afterwards, subjects were asked to rate the likelihood each stimulus was followed by a shock (explicit ratings). In the fMRI analyses, we identified the regions of the brain that showed significant CS+ vs. CS− responses during the conditioning phase in both groups. Those regions were then tested for generalization responses using an anatomical regions-of-interest approach and a mixed design ANOVA. Results: There were no between-group differences in CS+ vs. CS− responses of the brain during the conditioning phase. In both groups, CS+ > CS− activation was observed in the anterior insula and dorsal anterior cingulate cortex, whereas the reversed pattern (CS− > CS+) was observed in the ventromedial prefrontal cortex and angular gyri. During the generalization phase, patients with schizophrenia exhibited impaired generalization, both behaviorally (explicit ratings) and in the brain, most prominently in the right anterior insula, due to a lack of differentiation between the morphs and the CS−. This abnormality correlated with positive symptom severity. Conclusion: Schizophrenia patients are able to successfully acquire conditioned fear responses, but show impaired generalization of those fear memories. This impairment in fear generalization is associated with abnormal functioning of the anterior insula. These findings suggest that psychosis may arise in part from a deficit in the immediate retrieval of associative memory traces—a basic process that can be quantified as impaired fear generalization.