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It has recently been reported that secretin activates gene expression in the central nucleus of the amygdala in rats. To examine the neurophysiological effects of secretin on amygdalar activation in humans, the authors measured Blood Oxygen Level Dependent functional magnetic resonance imaging signal change during facial affect processing in a placebo-controlled double-blind study. The authors studied 12 healthy male subjects who were presented with three stimulus conditions: viewing happy, fearful, and neutral faces, before and after infusion with either secretin or placebo. To test whether treatment was associated with distinct patterns of activation, the two conditions (Pre and Post) were subjected to a subtraction analyses in SPM99 and hypotheses regarding the activation of the left and right amygdala were tested using a region-of-interest approach. Subtraction of treatment minus baseline activation during the fear condition yielded significant (p = .001) activation in the right amygdala and a nonsignificant increase in activation in the left amygdala. No significant differences were seen between the treatment conditions for the amygdala when viewing happy or neutral faces. These preliminary findings indicate that secretin may alter responsivity to affective stimuli. The presence of increased activation of the amygdala during the viewing of fearful faces is consistent with findings from animal studies and suggests a mechanism by which secretin may modulate social behavior.