Neural abnormalities in fear generalization in schizophrenia and associations with negative symptoms

Abstract Background Associative learning and memory processes, including the generalization of previously learned associations, may be altered in schizophrenia. Deficits in schizophrenia in stimulus generalization, one of the simpliest forms of memory, could interfere with the ability to efficiently categorize related, similar information, potentially leading to impairments in daily functioning. Methods To measure generalization in schizophrenia, 37 individuals with a non-affective psychotic disorder and 32 demographically-matched healthy control subjects underwent a Pavlovian fear conditioning and generalization procedure, which accounted for variation in perceptual ability across participants, while undergoing functional magnetic resonance imaging (fMRI). Skin conductance and fMRI responses to conditioned (CS+), control (CS-) and generalization stimuli were measured. Explicit memory ratings reflecting successful generalization were also collected following the scanning, as well as measures of symptom severity. Results Compared to healthy control subjects, individuals with non-affective psychotic disorders showed significant deficits in fear generalization across multiple measurements, with impairments in memory ratings and reductions in activation and deactivation of the Salience and Default Networks, respectively, during fear generalization. Moreover, in the psychotic disorder group, greater behavioral and neural abnormalities in generalization correlated with higher levels of negative symptoms. Conclusions Fear generalization is impaired in psychotic illness. Given that successful generalization relies on a dynamic balance between excitatory and inhibitory neurotransmission, these results reveal a potentially quantifiable mechanism linked to negative symptoms that may be investigated further in future human and experimental animal studies.