Amygdala-hippocampal involvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging

Previous functional neuroimaging studies have characterized brain systems m ediating associative learning using classical delay conditioning paradigms. In the present study, we used event-related functional magnetic resonance imaging to characterize neuronal responses mediating aversive trace conditi oning. During conditioning, neutral auditory tones were paired with an aver sive sound [unconditioned stimulus (US)]. We compared neuronal responses ev oked by conditioned (CS+) and nonconditioned (CS-) stimuli in which a 50% p airing of CS+ and the US enabled us to limit our analysis to responses evok ed by the CS+ alone. Differential responses (CS+ vs CS-), related to condit ioning, were observed in anterior cingulate and anterior insula, regions pr eviously implicated in delay fear conditioning. Differential responses were also observed in the amygdala and hippocampus that were best characterized with a time x stimulus interaction, indicating rapid adaptation of CS+-spe cific responses in medial temporal lobe. These results are strikingly simil ar to those obtained with a previous delay conditioning experiment and are in accord with a preferential role for medial temporal lobe structures duri ng the early phase of conditioning. However, an additional activation of an terior hippocampus in the present experiment supports a view that its role in trace conditioning is to maintain a memory trace between the offset of t he CS+ and the delayed onset of the US to enable associative learning in tr ace conditioning.