Appetitive and aversive olfactory learning in humans studied using event-related functional magnetic resonance imaging

Abstract

We combined event-related functional magnetic resonance imaging (fMRI) with olfactory classical conditioning to differentiate the neural responses evoked during appetitive and aversive olfactory learning. Three neutral faces [the conditioned stimuli (CS+)] were repetitively paired with pleasant, neutral, or unpleasant odors [the unconditioned stimuli (UCS)] in a partial reinforcement schedule. A fourth face was never paired to odor [the nonconditioned stimulus (CS-)]. Learning-related neural activity, comparing unpaired (face only) CS+ stimuli with CS-, showed valence-independent activations in rostral and caudal orbitofrontal cortex (OFC). Medial OFC responded to the appetitive (app) CS+, whereas lateral OFC responded to the aversive (av) CS+. Within nucleus accumbens, neural responses showed divergent activation profiles that increased with time in response to the appCS+ but decreased in response to the avCS+. In posterior amygdala, responses were elicited by the appCS+, which habituated over time. In temporal piriform cortex, neural responses were evoked by the avCS+, which progressively increased with time. These results highlight regional and temporal dissociations during olfactory learning and imply that emotionally salient odors can engender cross-modal associative learning. Moreover, the findings suggest that the role of human primary (piriform) and secondary olfactory cortices transcends their function as mere intermediaries of chemosensory information processing.

Fig. 1.

Differential reaction times. Condition-specific RTs were averaged across subjects over each of three successive blocks of the experiment. A, RT differences between an aversive CS+_U and CS− (mean ± SEM). Significant between-block differences were set at p < 0.05 and are indicated by asterisk. B, RT differences between an appetitive CS+_U and CS−. Significance,p < 0.05.

Fig. 2.

Valence-independent learning. A, Rostral orbitofrontal cortex. The SPM (threshold, p< 0.001) is overlaid on the axial (i) and coronal (ii) sections of a subject's normalized T1-weighted scan and depicts extensive bilateral activations in rostral areas of orbitofrontal cortex. In this and all subsequent figures, the right side of the brain corresponds to the right side of the image. B, Caudal orbitofrontal cortex.i, Neural activations in caudal orbitofrontal cortex are superimposed on a normalized T1-weighted coronal image (threshold,p < 0.001). ii, The learning-evoked activations depicted in i are illustrated inred (threshold, p < 0.001) and overlap the odor-evoked activations derived from the companion study (Gottfried et al., 2002), which are shown in blue(threshold, p < 0.005).

Fig. 3.

Neural activations evoked by appetitive olfactory learning. A, In the main effect of appetitive learning (appCS+_U − appCS−), BOLD activity was significantly increased within medial and anterior orbitofrontal cortex. The SPMs are superimposed on coronal (i) and axial (ii) sections of a T1-weighted scan (threshold,p < 0.001). B, C, Neural activations in bilateral nucleus accumbens (B) and posterior amygdala/medial temporal lobe (C) were revealed in the direct contrast of (appCS+_U − avCS+_U) and are depicted in coronal (i) and axial (ii) formats (threshold, p < 0.005).

Fig. 4.

Time-dependent response enhancements in nucleus accumbens elicited by appetitive learning. The main effect of (appCS+_U × time) relative to (appCS− × time) demonstrates increasing activity in right nucleus accumbens over the course of the experiment. SPMs are displayed on coronal (A) and axial (B) slices of a T1-weighted scan (threshold, p < 0.005).C, The contrasts of parameter estimates from the peak voxel within right nucleus accumbens are plotted for each subject, and the mean value (0.17) is indicated by a short horizontal bar.

Fig. 5.

Neural activations evoked by aversive olfactory learning. A, The main effect of aversive learning (avCS+_U − avCS−) showed responses in left lateral orbitofrontal cortex. The SPM is overlaid on coronal (i) and axial (ii) sections of a T1-weighted image and thresholded at p < 0.001.B, i, In the contrast of condition × time interactions (avCS+_U × time − avCS− × time), significant response increases were seen in anteromedial temporal lobe extending into temporal piriform cortex and periamygdaloid areas (threshold, p < 0.005). ii, Similar time-dependent enhancements of activity were detected in the direct comparison between (avCS+_U × time) and (appCS+_U × time) (threshold, p < 0.001). C, i, Time-dependent response decreases were observed in nucleus accumbens in the contrast of (avCS+_U × time − avCS− × time) (threshold,p < 0.005). ii, The contrasts of parameter estimates from the peak accumbens voxel are plotted for each subject, along with the mean value (0.12).

Fig. 6.

Divergent temporal profiles in nucleus accumbens. A, C, Neural activity in nucleus accumbens increased over time during appetitive olfactory learning.A, The percentage signal change of the fitted hemodynamic response in nucleus accumbens elicited by an appCS+_U stimulus (minus the CS− baseline) is plotted against repetition number for one subject and shows that repeated presentations of appCS+_U evoke progressive increases in the response signal. C, The contrasts of parameter estimates (appCS+_U − appCS−) (at 14, 16, −12) pooled across all subjects (means ± SEM) are depicted across successive thirds of the experiment and confirm an increasing temporal response profile at the group level. B, D, Activity in nucleus accumbens habituated over time during aversive olfactory learning.B, The plot of the percentage signal change elicited by avCS+_U (minus CS−) reveals a pattern in nucleus accumbens that habituates over repeated stimulus presentations (same subject as in A). D, Similarly, the group response profile of the contrast of parameter estimates (at −10, 16, −12) shows a steady decline over time.