Our data provide evidence suggesting that the recall of extinction memory in humans is mediated by a network of brain areas, including the VMPFC and the anterior hippocampus. Interestingly, a similar, although right-sided, VMPFC area to the one observed here shows increased cortical thickness in subjects with better extinction recall performance (Milad et al., 2005
). There was no activation to the CS+ relative to the CS− in this network in the conditioning context. That is, the network does not activate whenever an extinguished CS+ is presented but only when contextual information signals the appropriateness of inhibiting the CR. This network is therefore likely to form a neurobiological substrate for the context dependence of extinction recall (Bouton, 2004
), a hypothesis that existing animal (Sotres-Bayon et al., 2004
) and human (Phelps et al., 2004
; LaBar and Phelps, 2005
; Milad et al., 2005
) studies have not tested. The finding of extinction context-specific relative activations in our study [as opposed to the extinction-related deactivations observed previously by others (LaBar and Phelps, 2005
)] also supports the general idea that extinction (and its recall) is not simply a process of forgetting the CS–UCS association but consists in creating (and later recalling) a new CS–noUCS memory trace (Myers and Davis, 2002
; Bouton, 2004
; Delamater, 2004
Our data are consistent with the hypothesis that, during recall of extinction memory, the hippocampus processes contextual information supporting recall of that memory (Delamater, 2004
) and that this may confer (extinction) context dependence to CS+-evoked VMPFC activity. The reported correlations between hippocampus and VMPFC do not allow us to infer causality or directionality. We note, however, that a recent study of recall of extinction memory in which the test context was identical to the conditioning and extinction contexts (“AAA design”) found evidence of VMPFC, but not hippocampal, activation (LaBar and Phelps, 2005
). In an AAA design, the context provides ambiguous and thus essentially useless information with regard to the competition between fear and extinction memory, and, hence, the competition may simply be regulated by the relative strength of the two memory traces. As a consequence, recall of extinction memory in an AAA design may not require the hippocampus. The model is also supported by evidence that the hippocampus provides a major excitatory input to the VMPFC (for review, see Sotres-Bayon et al., 2004
) and that hippocampus-to-VMPFC projections are considerably stronger than VMPFC-to-hippocampus projections (Cavada et al., 2000
). It is noteworthy that, in the rat, hippocampal VMPFC afferents stem from subiculum and CA1 (Sotres-Bayon et al., 2004
), which corresponds to the location of the anterior hippocampal activation observed in this study ().
Rat data have shown that lesions of the entire hippocampus or fornix do not impair context-dependent recall of extinction memory (Wilson et al., 1995
; Frohardt et al., 2000
). A study in human patients yielded similar results (LaBar and Phelps, 2005
). However, in these experiments, lesions were present before conditioning and extinction. This leaves open the possibility that redundant systems provided for encoding and recall of context information in the hippocampus-lesioned subjects. We suggest that the VMPFC normally receives contextual information from the anterior hippocampus but can call on inputs from other poly-modal areas (Heidbreder and Groenewegen, 2003
) when this hippocampus area is dysfunctional.
Our data provide only limited evidence for the alternative model by Hobin et al. (2003)
positing a role of the posterior hippocampus in regulating the fear versus extinction memory competition. Although we found the predicted activation of right posterior hippocampus during recall of fear memory, this activation was not conditioning context specific. Also, we did not find the predicted negative correlation with VMPFC that could have been interpreted as indexing suppression of extinction memories in a non-extinction context. Nevertheless, the idea that the hippocampus supports context-dependent recall of fear memory has recently been strengthened by the finding of impaired context-specific reinstatement in two hippocampal patients (LaBar and Phelps, 2005
). Unfortunately, no information about the exact anatomy of the lesion was available. Furthermore, the lesions occurred before conditioning and extinction. We thus do not want to exclude a contribution of posterior hippocampus to the inhibition of extinction recall in humans. However, any contribution has to be weighed against an active contribution from more anterior hippocampal areas, supporting the recall of extinction memory.
Any recall test in the absence of paired UCSs is necessarily accompanied by ongoing extinction, usually restricting CR recovery to one or a few initial CS presentations. fMRI design constraints, however, require that conditions are presented repeatedly, forcing us to induce CR recovery over 16 blocks of context A. This was achieved here by combining renewal with reinstatement. In renewal, CS-induced CR recovery is facilitated by presenting the CS in the same context as during initial conditioning. In reinstatement, CS-evoked recall of fear memory is facilitated by unpaired UCS presentations in the same context in which the CS is presented. A limitation of this study is therefore that we are unable to differentiate between renewal and reinstatement effects on recall of fear memory. This makes any conclusions derived about recall of fear memory (such as about a possible role of the posterior hippocampus) less strong than conclusions about context-dependent recall of extinction memory, for which purpose this study was explicitly designed.
Renewal/reinstatement on day 2 was evident from increased reaction times to the CS+ relative to the CS−, although, unexpectedly, there were no skin conductance differences. We suggest that this behavioral dissociation can be understood by considering that conditioning is expressed in a variety of behaviors, making it conceivable that not all behavioral expressions of a CR are produced with each CS presentation. Such a scenario is more likely where CS presentations are non-reinforced, possibly resulting in on-line extinction, such as on day 2 here (see above). Dissociations between behavioral and physiological measures of emotional reactions have also been observed in other studies (Johnstone and Page, 2004
). It should be noted that reaction times are a valid and widely used method to measure CRs in humans (Critchley et al., 2002
; Gottfried et al., 2002
; Dirikx et al., 2004
; Gottfried and Dolan, 2004
; Hermans et al., 2005
). They are also widely used in the assessment of other emotional responses, such as the attention-grabbing effect of aversive stimuli, in which their use has plausible theoretical grounds [namely interference with cognitive processing by aversive stimuli (Mathews et al., 1997
)]. Nevertheless, the observed dissociation suggests caution in the interpretation of our data and warrants independent confirmation of our results by future studies.
We did not observe any significant negative correlation between VMPFC and amygdala. This may reflect the fact that VMPFC-dependent suppression of CS+-evoked amygdala output involves both excitation (of direct VMPFC target neurons in lateral amygdala or intercalated cell masses) and inhibition (of amygdala output neurons, possibly by inhibitory VMPFC target neurons) (Quirk et al., 2003
; Rosenkranz et al., 2003
; Pare et al., 2004
). Given the low spatial resolution of fMRI, both effects may cancel each other out.
We have discussed our findings in terms of extinction, but it is important to acknowledge that a conditioned inhibition (CI) framework provides an alternative account of our data. In CI, conditioning to a first CS (“target” stimulus T) is followed by a training phase in which T is presented together with a second CS (“feature” stimulus F) but without the UCS (Pavlov, 1927
). Hence, F comes to predict absence of the UCS, resulting in an inhibitory F–noUCS memory trace. In the present experiment, the CS+ could be conceptualized as T and the extinction context B as F. CR inhibition would then be mainly conveyed by a F–noUCS association (i.e., the extinction context itself) and not, as in the case of extinction, by a CS+–noUCS association (the extinction memory). Nevertheless, current models of CI (Pearce and Hall, 1980
; Wagner and Brandon, 1989
; Nelson and Bouton, 1997
) assume that, similar to extinction, T (i.e., the CS+) also acquires some inhibitory properties. Furthermore, in the case of extinction, when one recalls an extinction memory in its extinction context, the context will contribute to the activation of the inhibitory association of the CS+, that is, will contribute to inhibition. Therefore, CI and the type of contextualized extinction investigated here are conceptually hard to distinguish. It should also be noted that current theories do not distinguish between an “extinction”–inhibition and a “CI”–inhibition but treat all inhibition the same, suggesting that either account is appropriate to describe our data.
Little has been known about the context-dependent recall of extinction memory in humans. A key feature of this study is that our design allows delineation of the neural circuitry involved in that function, using a psychological manipulation that engenders recall of extinction memory in the appropriate context. Clinically, contextual restrictions on extinction can considerably complicate anxiety therapy, sometimes resulting in fear recovery in nontherapy contexts even after successful fear extinction. For therapeutic purposes, therefore, it may often be desirable to create noncontextualized extinction memories. Our data suggest that such decontextualization may be achieved by rendering the VMPFC-dependent recall of extinction memories hippocampus independent. New pharmacological treatments facilitating the consolidation of extinction memories (Walker et al., 2002
; Ressler et al., 2004
) (for review, see Richardson et al., 2004
) may also facilitate such context-independent activation of the VMPFC (Ledgerwood et al., 2004