Evidence That Altered Amygdala Activity in Schizophrenia Is Related to Clinical State and Not Genetic Risk

Abstract

Objective-Although amygdala dysfunction is reported in schizophrenia, it is unknown whether this deficit represents a heritable phenotype that is related to risk for schizophrenia or whether it is related to disease state. The purpose of the present study was to examine amygdala response to threatening faces among healthy siblings of schizophrenia patients in whom a subtler heritable deficit might be observed.Method-Participants were 34 schizophrenia patients, 29 unaffected siblings, and 20 healthy comparison subjects. Blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted during an implicit facial information processing task. The N-back working memory task, which has been shown to elicit prefrontal cortex abnormalities in unaffected siblings of schizophrenia patients, was employed as a positive experimental control.Results-Schizophrenia patients demonstrated a deficit in amygdala reactivity to negative face stimuli and an alteration, correlated with neuroleptic drug dosage, in the functional coupling between the amygdala and subgenual cingulate. In contrast, unaffected siblings showed a pattern that was not statistically different from that of healthy comparison subjects. During the N-back working memory task, both schizophrenia patients and their unaffected siblings demonstrated a pattern of inefficient prefrontal cortex engagement, which is consistent with earlier evidence that this pattern is related to genetic risk for schizophrenia.Conclusions-These data suggest that the pathophysiological mechanism underlying the inability of individuals with schizophrenia to normally engage the amygdala in processing fearful and angry facial representations is more likely a phenomenon related to the disease state, specifically to treatment.Face processing, which is integral to the processing of salient environmental cues during social interactions, is critically dependent on amygdala functioning (1). Reduced amygdala response to fearful faces has been found in individuals with schizophrenia (2,3). The response to fearful faces is widely used as a paradigm to examine the reactivity of the amygdala to salient stimuli, and the underlying circuit has been shown to be modulated by genes linked to temperament and emotional response-for example, the serotonin transporter SLC6A4 genotype (4-7), catechol-O-methyltransferase (COMT) genotype (8,9), and monamine oxidase A (MAO-A)Address correspondence and reprint requests to Dr. Weinberger, Genes, Cognition, and Psychosis Program, IRP, NIMH, NIH, Rm. 4S-235, 10 Center Dr., Bethesda, MD 20892; daniel.weinberger@mail.nih.gov NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript genotype (10). These observations raise questions regarding the nature of face processing deficits associated with schizophrenia and the extent to which these deficits are based on genetic and nongenetic factors. One method with the potential to differentiate genetic versus secondary risk factors associated with schizophrenia is to study face ...

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