Our findings from two independently tested fear expression paradigms considerably advance our understanding of medial prefrontal function in fear/anxiety: they strongly indicate that a previously described threat-responsive rostral dmPFC/dACC area makes at most a minor contribution to fear learning while at the same time they confirm the threat-responsiveness of this region. That is, the area was primarily active during a situation of pure fear appraisal/expression in the absence of fear learning (UF-Test) but tended to start responding already during the course of prior conditioning. In addition, the observation from the uninstructed fear expression paradigm (UF, study 2) that the area only started to respond after peripheral-physiological conditioned responding (SCRs) had already been registered further replicates previous results that the area is not directly involved in physiological fear expression. In combination with the data discussed below, this supports our hypothesis that one of the major functions of the rostral dmPFC/dACC is the appraisal of threat.
Threat situations induce a host of processes including attentional deployment, appraisals of the threat content of the situation, and subsequent autonomic, hormonal, motor and subjective-experiential threat reactions. Threat reactions change the external and internal environment and can therefore become emotional stimuli in their own right, inducing a new cycle of attending, appraising and reacting. Finally, the described emotion generation processes are often intermingled with associative learning and recall of threat contingencies. This complexity of the organism’s threat response is a challenge for any functional-neuroanatomical examination. Nevertheless, the current state of research permits some relatively safe conclusions with regards to rostral dmPFC/dACC function in threat. First, the present data and two aforementioned studies 
conclusively show that neural activity in the rostral dmPFC/dACC is dissociated from responding at the peripheral-physiological level, making it unlikely that the area is directly engaged in the expression of physiological fear responses. As argued earlier, better candidates for this function can be found in more posterior parts of the dmPFC/dACC 
(reviewed in 
), or the insular cortex 
. Second, the area is particularly active when threat is processed consciously or explicitly 
, a claim that was not tested in the present study but that resonates with evidence from studies outside the domain of fear where the rostral dmPFC is active when emotional stimuli are evaluated explicitly (see 
for meta-analysis). Third, the area is down-regulated when threat is reappraised in a less negative fashion 
and hyperactive in subjects that catastrophize 
, suggesting the area is particularly concerned with the negative aspects of a threat situation. In sum, these data suggests a conscious negative threat appraisal function for the rostral dmPFC/dACC. However, it would be premature to conclude that the area is exclusively concerned with valence-specific negative threat appraisal but it may have a more general function in conscious emotional evaluation irrespective of stimulus valence 
. A possible alternative explanation that the area supports fear acquisition has been made unlikely by our present findings. Yet another possible alternative explanation for rostral dmPFC/dACC activation during threat is that it mediates the subjective-experiential, or feeling, aspect of fear. Arguing against this explanation is the observation that subjects still report high levels of subjective anxiety even if rostral dmPFC/dACC activation is entirely abolished 
. We emphasize however that the latter result was obtained on the basis of post-hoc anxiety ratings and should therefore be tested again in an optimized paradigm.
One question mark that the present results raise is why subjects in study 2 (UF) explicitly evaluated CSs as predicting a UCS and being of negative valence already during the conditioning runs, but only strongly activated their rostral dmPFC/dACC later, during testing. If the rostral dmPFC/dACC is responsible for explicit threat appraisals, its activation should parallel those. One possibility might be that the area is less interested in the threatening properties of external stimuli or their contingencies but in the internal consequences of a threat situation. It might thus monitor and judge changes in attention, bodily states, or feelings that occur during threat. In catastrophizers, the negative interpretation of such internal changes as signals of impending harm can cause a state of “fear of fear” that may contribute to the development of pathological anxiety 
. Such an interpretation of our findings would tie in with the observation that normal subjects who are genetically pre-disposed to develop panic disorder show a hyper-activation of the rostral dmPFC/dACC during Pavlovian fear conditioning that correlates with a subjective over-estimation of their conditioned fear reactions 
. The interpretation is also supported by a very recent study showing rostral dmPFC/dACC activity during instructed fear of an interoceptive threat (a breathing challenge) that was correlated with a trait measure of fear of somatic symptoms 
The present design where reinforcement was deliberately omitted during fear testing has the unavoidable disadvantage that we cannot definitively exclude extinction learning as an alternative explanation for dmPFC/dACC activation at test. Extinction is thought to result from the prediction error that is registered when an expected aversive reinforcement does not occur 
. In study 1 (IF), we tried to prevent such expectation violation by only instructing subjects that the UCS “might” occur. Nevertheless, subjects’ post-experimental self-report suggest they did update their UCS expectancies to a certain degree, even though this did not express in a concomitant reduction of fear responding (SCRs). Study 2 (UF) contained two elements that we hoped would slow down extinction during testing: i) a low reinforcement ratio of 50% during conditioning and ii) the presentation of a single paired “refresher” CS+ at the outset of the test run that, together, should relatively reduce prediction errors when the UCS is omitted at test. To better assess potential expectancy changes, we further asked subjects to provide quantitative expectancy ratings before and after every run. In contrast to study 1, there was no evidence for any expectancy updating. Furthermore, as in study 1, there was no evidence for actual extinction of conditioned skin conductance responding. Both would speak against the occurrence of prediction errors. Nevertheless, it is theoretically possible that subjects only change their expectations (and consequentially their conditioned responding) after having sampled a sufficient amount of prediction errors. The question whether dmPFC/dACC activation might reflect a prediction error-type mechanism rather than threat appraisal can thus not be conclusively answered from our data. However, the presence of rostral dmPFC/dACC activation in IF paradigms where reinforcement does occur at a rate corresponding to the instruction 
as well as the consistent observation that extinction is spared after dorsal mPFC lesions in rodents 
would suggest the question should be answered in the negative. Further research will be required to clarify this issue. A final limitation of our study that needs to be mentioned is that all findings reported here emanate from analyses that were secondary to the original purposes of the two studies.
To conclude, we have presented and discussed convergent evidence that speaks for an involvement of the rostral dmPFC/dACC in conscious negative threat appraisal. Cognitive psychotherapy tries to heal pathological anxiety by making patients aware of the unrealistic nature of such appraisals and teaching them to replace their negative thoughts by a more positive interpretation of the feared situation. It is an intriguing speculation that the rostral dmPFC/dACC might be at the source of negative thinking in pathological anxiety and that therapeutic progress might express in a silencing of rostral dmPFC/dACC activation. It would also be interesting to investigate whether rostral dmPFC/dACC inhibition, perhaps possible with tools like transcranial direct current stimulation, can alleviate negative cognitions and accompanying anxiety. In turn, in a safe therapy setting a patient might benefit from dmPFC/dACC stimulation when being guided to re-appraise fear or anxiety inducing situations or memories. A recent finding that threat enhances rostral dmPFC/dACC coupling with the amygdala 
suggests the area could be a promising entry point into the fear system. The present line of research thus opens up a potentially promising avenue for translational research.