Negative emotional stimuli activate a broad network of brain regions, including the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. An early influential view dichotomized these regions into dorsal–caudal cognitive and ventral–rostral affective subdivisions. In this review, we examine a wealth of recent research on negative emotions in animals and humans, using the example of fear or anxiety, and conclude that, contrary to the traditional dichotomy, both subdivisions make key contributions to emotional processing. Specifically, dorsal–caudal regions of the ACC and mPFC are involved in appraisal and expression of negative emotion, whereas ventral–rostral portions of the ACC and mPFC have a regulatory role with respect to limbic regions involved in generating emotional responses. Moreover, this new framework is broadly consistent with emerging data on other negative and positive emotions.

Given the complexity [] and multidimensional nature [] of emotional responses, we address the specific functions or processes that constitute an emotional reaction, regardless of whether they are classically seen as emotional (e.g. a withdrawal response or a feeling) or cognitive (e.g. attentional focusing on a relevant stimulus). We also distinguish between processes involved in emotional stimulus appraisal and consequential response expression [] and those involved in emotion regulation. Regulation occurs when stimuli induce conflicting appraisals and hence incompatible response tendencies or when goal-directed activity requires suppression of interference from a single, emotionally salient, task-irrelevant stimulus source. We found that an appraisal or expression versus regulation contrast provides a robust framework for understanding ACC and mPFC function in negative emotion.

Here, we review recent human neuroimaging, animal electrophysiology, and human and animal lesion studies that have produced a wealth of data on the role of the ACC and mPFC in the processing of anxiety and fear. We chose to focus primarily on the negative emotions of anxiety and fear because they are by far the most experimentally tractable and most heavily studied, and they afford the closest link between animal and human data. We subsequently briefly examine whether a conceptual framework derived from fear and anxiety can be generalized to other emotions.

Undoubtedly the most influential functional parcellation of this type has been the proposal that there exists a principal dichotomy between caudal–dorsal midline regions that serve a variety of cognitive functions and rostral–ventral midline regions that are involved in some form of emotional processing []. However, even this broadly and long-held view of basic functional specialization in these regions has been shaken by considerable evidence over the past decade indicating that many types of emotional processes reliably recruit caudal–dorsal ACC and mPFC regions [].

Although the medial walls of the frontal lobes, comprising the anterior cingulate cortex (ACC) and the medial prefrontal cortex (mPFC), have long been thought to play a critical role in emotional processing [], it remains uncertain what exactly their functional contributions might be. Some investigators have described evaluative (appraisal) functions of the ACC and mPFC, such as representation of the value of stimuli or actions [] and the monitoring of somatic states []. Others hold that the ACC is primarily a generator of physiological or behavioral responses []. Still others have described a regulatory role for these regions, such as in the top-down modulation of limbic and endocrine systems for the purpose of emotion regulation []. An additional source of uncertainty lies in the way in which any one of these proposed functions might map onto distinct subregions of the ACC or mPFC ( Box 1 ).

Much like the nearby ACC subregions, the supplementary motor area (SMA) is heavily interconnected with primary motor cortex and is the origin for direct corticospinal projections []. The pre-SMA, by contrast, is connected with lateral prefrontal cortices, but not with primary motor cortex []. Premotor and lateral prefrontal connections are also present, albeit to a lesser degree, in the dmPFC []. Thus, the patterns of connectivity are similar between abutting ACC and mPFC subregions, with the difference being primarily in the density of limbic connectivity, which is substantially greater in the ACC.

Like the ACC ( Figure I ), the mPFC can be divided into several functionally distinct subregions, although borders between these subregions are generally less clear, and differential anatomical connectivity is less well described. Amygdalar, hypothalamic and PAG connectivity with mPFC subregions is considerably lighter than the connectivity of adjacent ACC subregions, with the strongest connections observed for the ventromedial (vmPFC) and dorsomedial PFC (dmPFC) [].

Topographic organization of connections between the hypothalamus and prefrontal cortex in the rhesus monkey.

Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata.

ACC subregions can also be distinguished based on connectivity with premotor and lateral prefrontal cortices, which are heaviest in the pdACC and adACC []. In summary, the pattern of anatomical connectivity supports an important role for the sgACC, pgACC and adACC in interacting with the limbic system, including its effector regions, and for the adACC and pdACC in communicating with other dorsal and lateral frontal areas that are important for top-down forms of regulation [].

These subdivisions are also reflected in patterns of connectivity. Connectivity with core emotion-processing regions such as the amygdala, PAG and hypothalamus is strong throughout the sgACC, pgACC and adACC, but very limited in the pdACC []. In general, cingulo–amygdalar connectivity is focused on the basolateral complex of the amygdala.

Topographic organization of connections between the hypothalamus and prefrontal cortex in the rhesus monkey.

Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata.

Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala.

Within the ACC, a subdivision can be made between a more ventral portion, comprising areas 24a, 24b, 24c, 25, 32 and 33 [pregenual (pgACC) and subgenual ACC (sgACC) in Figure I ] and a more dorsal portion, comprising areas 24a′, 24b′, 24c′, 24d, 32′ and 33 [dorsal ACC (dACC) in Figure 1 ]. This distinction is consistent with that of Vogt and colleagues between an anterior and a midcingulate cortex []. In the dACC, a further distinction exists between anterior and posterior portions of the dACC (adACC and pdACC), similar to partitioning of the midcingulate into anterior and posterior portions by Vogt et al. [] and consistent with partitioning between rostral and caudal cingulate zones [].

Prefrontal involvement in the regulation of emotion: convergence of rat and human studies.

Resolving emotional conflict: a role for the rostral anterior cingulate cortex in modulating activity in the amygdala.

How do you feel – now? The anterior insula and human awareness.

Fear conditioning and extinction in humans

The paradigms used in the acquisition and extinction of learned fear are particularly valuable for isolating the neural substrates of fear processing because the anticipatory fear or anxiety triggered by the previously neutral conditioned stimulus (CS) can be dissociated from the reaction to the aversive unconditioned stimulus (US) per se. This is not possible in studies that, for example, use aversive images to evoke emotional responses. Furthermore, comparison between fear conditioning and fear extinction facilitates an initial coarse distinction between regions associated with either the appraisal of fear-relevant stimuli and generation of fear responses (fear conditioning), or the inhibitory regulation of these processes (extinction).

13 Etkin A.

Wager T.D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. 14 Mechias M.L.

et al. A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. 18 LaBar K.S.

Cabeza R. Cognitive neuroscience of emotional memory. Figure 1 a), as well as during instructed fear paradigms, which circumvent fear learning (b). Likewise, sympathetic nervous system activity correlates positively primarily with dorsal ACC and mPFC regions and negatively primarily with ventral ACC and mPFC regions, which supports a role for the dorsal ACC and mPFC in fear expression (c). During within-session extinction, activation is observed in both the dorsal and ventral ACC and mPFC (d), whereas during subsequent delayed recall and expression of the extinction memory, when the imaging data are less confounded by residual expression of fear responses, activation is primarily in the ventral ACC and mPFC (e). Information on the studies selected for this and all following peak voxel plots can be found in the Activation foci associated with fear and its regulation. Predominantly dorsal ACC and mPFC activations are observed during classical (Pavlovian) fear conditioning (), as well as during instructed fear paradigms, which circumvent fear learning (). Likewise, sympathetic nervous system activity correlates positively primarily with dorsal ACC and mPFC regions and negatively primarily with ventral ACC and mPFC regions, which supports a role for the dorsal ACC and mPFC in fear expression (). During within-session extinction, activation is observed in both the dorsal and ventral ACC and mPFC (), whereas during subsequent delayed recall and expression of the extinction memory, when the imaging data are less confounded by residual expression of fear responses, activation is primarily in the ventral ACC and mPFC (). Information on the studies selected for this and all following peak voxel plots can be found in the online supplemental material Several recent quantitative meta-analyses of human neuroimaging studies examined activations associated with fear CS presentation compared to a control CS never paired with the US []. In Figure 1 a we present plots of the location of each activation peak reported in the ACC or mPFC in the relevant fear conditioning studies, collapsing across left and right hemispheres. It is readily apparent that activations in fear conditioning studies are not evenly distributed throughout the ACC and mPFC, but rather are clustered heavily within the dorsal ACC (dACC), dorsomedial PFC (dmPFC), supplementary motor area (SMA) and pre-SMA. These activations, however, might reflect a variety of different processes that occur simultaneously or in rapid temporal succession, for example CS appraisal and expression of conditioned responses (CRs). These processes are intermixed with, and supported by, learning processes, namely, acquisition, consolidation and storage of a fear memory (CS–US association), and retrieval of the fear memory on subsequent CS presentations.

14 Mechias M.L.

et al. A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. 19 Klucken T.

et al. Neural, electrodermal and behavioral response patterns in contingency aware and unaware subjects during a picture–picture conditioning paradigm. 20 Kalisch R.

et al. The NMDA agonist D-cycloserine facilitates fear memory consolidation in humans. 2 Kalisch R.

et al. Levels of appraisal: a medial prefrontal role in high-level appraisal of emotional material. 14 Mechias M.L.

et al. A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. 21 Raczka K.A.

et al. A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing. The acquisition component of fear conditioning can, to some extent, be circumvented by instructing subjects about CS–US contingencies at the beginning of an experiment. Such instructed fear experiments nevertheless also consistently activate the dorsal ACC and mPFC ( Figure 1 b) []. Similarly, recalling and generating fear in the absence of reinforcement several days after conditioning activate dorsal midline areas, and are not confounded by fear learning []. Rostral parts of the dorsal ACC/mPFC are specifically involved in the (conscious) appraisal, but not direct expression, of fear responses, as shown by reduction of rostral dACC and dmPFC activity to threat by high working memory load in the context of unchanged physiological reactivity [], and correlations of rostral dACC and dmPFC activity with explicit threat evaluations but not physiological threat reactions [].

22 Critchley H.D.

et al. Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. 23 Gentil A.F.

et al. Physiological responses to brain stimulation during limbic surgery: further evidence of anterior cingulate modulation of autonomic arousal. Response expression, conversely, seems to involve more caudal dorsal areas in SMA, pre-SMA and pdACC, and caudal parts of dmPFC and adACC, although some of the evidence for this contention is indirect and based on studies of the arousal component inherent to most fear and anxiety responses. For example, Figure 1 c shows clusters that correlate with sympathetic nervous system activity, irrespective of whether the context was fear-related or not. Positive correlations are found throughout the mPFC, but are again primarily clustered in mid-to-caudal dorsal mPFC areas. Lesion [] and electrical stimulation studies [] confirmed this anatomical distribution.

24 Milad M.R.

et al. A role for the human dorsal anterior cingulate cortex in fear expression. 25 Wager T.D.

et al. Brain mediators of cardiovascular responses to social threat: part I: Reciprocal dorsal and ventral sub-regions of the medial prefrontal cortex and heart-rate reactivity. 26 Meyer G.

et al. Stereotactic cingulotomy with results of acute stimulation and serial psychological testing. 27 Critchley H.D.

et al. Neural systems supporting interoceptive awareness. 27 Critchley H.D.

et al. Neural systems supporting interoceptive awareness. Box 2 Studies of fear conditioning and extinction in rodents 74 Sotres-Bayon F.

Quirk G.J. Prefrontal control of fear: more than just extinction. 75 Burgos-Robles A.

et al. Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure. 76 Herry C.

et al. Plasticity in the mediodorsal thalamo–prefrontal cortical transmission in behaving mice. 77 Resstel L.B.

et al. The expression of contextual fear conditioning involves activation of an NMDA receptor–nitric oxide pathway in the medial prefrontal cortex. 78 Blum S.

et al. A role for the prefrontal cortex in recall of recent and remote memories. 79 Corcoran K.A.

Quirk G.J. Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. 80 Laurent V.

Westbrook R.F. Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction. 81 Laviolette S.R.

et al. A subpopulation of neurons in the medial prefrontal cortex encodes emotional learning with burst and frequency codes through a dopamine D4 receptor-dependent basolateral amygdala input. 82 Quirk G.J.

et al. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. 83 Runyan J.D.

et al. A role for prefrontal cortex in memory storage for trace fear conditioning. 84 Sierra-Mercado Jr., D.

et al. Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction. 85 Morgan M.A.

LeDoux J.E. Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. 86 Maaswinkel H.

et al. Effects of an electrolytic lesion of the prelimbic area on anxiety-related and cognitive tasks in the rat. 87 Shah A.A.

Treit D. Excitotoxic lesions of the medial prefrontal cortex attenuate fear responses in the elevated-plus maze, social interaction and shock probe burying tests. A rich literature has examined the role of the rodent medial frontal cortex in the acquisition and extinction of conditioned fear, as well as the expression of conditioned and unconditioned fear []. These studies facilitate a greater degree of causal inference than imaging studies. Much like the human dorsal ACC and mPFC, the rodent mPFC is strongly activated during fear conditioning []. Lesion or acute inactivation studies have revealed a role for the ventrally located infralimbic (IL) and dorsally located prelimbic (PL) subregions in conditioned fear expression when recall tests are performed within a few days after initial conditioning []. Interestingly, the mPFC does not seem to be required during fear acquisition itself, as evidenced by intact initial fear learning after disruption of IL or PL prior to conditioning []. As with expression of fear memories, activity in the rodent mPFC is also required for expression of unconditioned fear []. 80 Laurent V.

Westbrook R.F. Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction. 82 Quirk G.J.

et al. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. 84 Sierra-Mercado Jr., D.

et al. Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction. 88 Lebron K.

et al. Delayed recall of fear extinction in rats with lesions of ventral medial prefrontal cortex. 85 Morgan M.A.

LeDoux J.E. Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. 89 Hugues S.

et al. Postextinction infusion of a mitogen-activated protein kinase inhibitor into the medial prefrontal cortex impairs memory of the extinction of conditioned fear. 80 Laurent V.

Westbrook R.F. Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction. 82 Quirk G.J.

et al. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. 84 Sierra-Mercado Jr., D.

et al. Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction. 88 Lebron K.

et al. Delayed recall of fear extinction in rats with lesions of ventral medial prefrontal cortex. In terms of extinction, the recall and expression of an extinction memory more than 24h after learning requires activity in IL [] and to some degree PL []. By contrast, within-session extinction of CRs during repeated non-reinforced presentations of the CS does not require activity in IL or PL []. Thus, the role of the mPFC during extinction closely follows its role during fear conditioning: it is required for recall or expression, but not for initial acquisition. 90 al Maskati H.A.

Zbrozyna A.W. Stimulation in prefrontal cortex area inhibits cardiovascular and motor components of the defence reaction in rats. 91 Milad M.R.

Quirk G.J. Neurons in medial prefrontal cortex signal memory for fear extinction. 92 Vidal-Gonzalez I.

et al. Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. 93 Zbrozyna A.W.

Westwood D.M. Stimulation in prefrontal cortex inhibits conditioned increase in blood pressure and avoidance bar pressing in rats. 90 al Maskati H.A.

Zbrozyna A.W. Stimulation in prefrontal cortex area inhibits cardiovascular and motor components of the defence reaction in rats. 91 Milad M.R.

Quirk G.J. Neurons in medial prefrontal cortex signal memory for fear extinction. 92 Vidal-Gonzalez I.

et al. Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. 93 Zbrozyna A.W.

Westwood D.M. Stimulation in prefrontal cortex inhibits conditioned increase in blood pressure and avoidance bar pressing in rats. 92 Vidal-Gonzalez I.

et al. Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Electrical microstimulation of the rodent mPFC generally does not directly elicit fear behavior or produce overt anxiolysis, but rather exerts a modulatory function, gating behavioral output elicited by external fear-eliciting stimuli or by direct subcortical stimulation []. Curiously, given the role of the mPFC in fear expression, it has been found that these effects are generally, but not exclusively, fear-inhibitory and occur with stimulation in all mPFC subregions []. Of note, however, one recent study found a fear-enhancing effect of PL stimulation, but a fear-inhibiting effect of IL stimulation []. Together, these findings suggest that a model of mPFC function in fear or extinction must account for interactions of the mPFC with other elements of the fear circuit, because the mPFC itself functions primarily by modifying activity in other brain areas. 94 Quirk G.J.

et al. Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. 95 Rosenkranz J.A.

et al. The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli. 96 Likhtik E.

et al. Prefrontal control of the amygdala. 97 Amano T.

et al. Synaptic correlates of fear extinction in the amygdala. 98 Ehrlich I.

et al. Amygdala inhibitory circuits and the control of fear memory. 99 McDonald A.J.

et al. Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat. 100 Vertes R.P. Differential projections of the infralimbic and prelimbic cortex in the rat. With respect to one important interacting partner, the amygdala, it has been reported that stimulation in the IL or PL inhibits the activity of output neurons in the central amygdalar nucleus (CEA) [], as well as the basolateral amygdalar complex (BLA) []. IL and PL stimulation can also directly activate BLA neurons []. Thus, the mPFC can promote fear expression through BLA activation and can inhibit amygdala output through CEA inhibition. CEA inhibition, however, is achieved through the action of excitatory glutamatergic mPFC projections onto inhibitory interneurons in the amygdala, probably through the intercalated cell masses []. Innervation of the intercalated cell masses originates predominantly from IL rather than PL [], which supports a preferential role for IL in inhibitory regulation of the amygdala. Considering these data in conjunction with observations that dACC activity correlates with fear-conditioned skin conductance responses [] and with increases in heart rate induced by a socially threatening situation [], as well as findings that direct electrical stimulation of the dACC can elicit subjective states of fear [], strongly suggests that the dorsal ACC and mPFC are involved in generating fear responses. Neuroimaging studies of autonomic nervous system activity also indirectly suggest that the same areas do not exclusively function in response expression, but might also support appraisal processes. For example, the dorsal ACC and mPFC are associated with interoceptive awareness of heart beats [], and, importantly, recruitment of the dorsal ACC and mPFC during interoceptive perception is positively correlated with subjects’ trait anxiety levels []. Thus, the dorsal ACC and mPFC seem to function generally in the appraisal and expression of fear or anxiety. These studies leave uncertain the role that the dorsal ACC and mPFC might play in the acquisition of conditioned fear, although converging evidence from studies in rodents ( Box 2 ) suggests only a minor role in acquisition.

28 Bouton M.E. Context and behavioral processes in extinction. 29 Delamater A.R. Experimental extinction in Pavlovian conditioning: behavioural and neuroscience perspectives. 30 Myers K.M.

Davis M. Behavioral and neural analysis of extinction. 31 Schiller D.

et al. From fear to safety and back: reversal of fear in the human brain. 32 Mobbs D.

et al. From threat to fear: the neural organization of defensive fear systems in humans. 33 Milad M.R.

et al. Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. 34 Phelps E.A.

et al. Extinction learning in humans: role of the amygdala and vmPFC. To elucidate how fear is regulated, we next discuss activations associated with extinction of learned fear. In extinction, the CS is repeatedly presented in the absence of reinforcement, leading to the formation of a CS–no US association (or extinction memory) that competes with the original fear memory for control over behavior []. Hence, extinction induces conflicting appraisals of, and response tendencies to, the CS because it now signals both threat and safety, a situation that requires regulation, as outlined above. We further distinguish between within-session extinction ( Figure 1 d, day 1) and extinction recall, as tested by CS presentation on a subsequent day ( Figure 1 e, day 2). Within-session extinction is associated with activation in both the dorsal ACC and mPFC (dACC, dmPFC, SMA and pre-SMA) and the ventral ACC and mPFC (pgACC and vmPFC; Figure 1 d). Given the close association of dorsal ACC and mPFC with fear conditioning responses, it should be noted that the activations observed within these regions during fear extinction might in fact reflect remnants of fear conditioning, because in early extinction trials the CS continues to elicit a residual CR. Activation within the ventral ACC and mPFC is thus a candidate neural correlate of the fear inhibition that occurs during extinction (for convergent rodent data, see Box 2 ). Accordingly, acute reversal of a fear conditioning contingency, during which a neutral, non-reinforced, CS is paired with an aversive stimulus, whereas the previously reinforced CS is not and now inhibits fear, is associated with activation in the pgACC []. Likewise, exposure to distant threat is associated with ventral ACC and mPFC activation, presumably acting in a regulatory capacity to facilitate planning of adaptive responses, whereas more imminent threat is associated with dorsal ACC and mPFC activation, which is consistent with greater expression of fear responses []. Along with ventral ACC and mPFC activation during extinction, decreases in amygdalar responses have also been reported [], consistent with the idea that amygdalar inhibition is an important component of extinction.

25 Wager T.D.

et al. Brain mediators of cardiovascular responses to social threat: part I: Reciprocal dorsal and ventral sub-regions of the medial prefrontal cortex and heart-rate reactivity. 35 Wager T.D.

et al. Brain mediators of cardiovascular responses to social threat, part II: Prefrontal-subcortical pathways and relationship with anxiety. In support of this conclusion, recall of extinction more than 24h after conditioning, a process that is less confounded by residual CRs, yields primarily ventral ACC and mPFC activations (pgACC, sgACC, vmPFC; Figure 1 e). It should be stressed, however, that extinction, like conditioning, involves multiple component processes, including acquisition, consolidation, storage and retrieval of the extinction memory, and the related appraisal of the CS as safe, of which CR inhibition is only the endpoint. The limited number of human neuroimaging studies of extinction do not allow a reliable parcellation of these processes, although a rich literature on rodents suggests that, like for fear conditioning, the role of the mPFC is primarily in expression rather than acquisition of inhibitory fear memories ( Box 2 ). Moreover, our conclusions are also supported by findings of negative correlations primarily between ventral areas (pgACC and vmPFC) and sympathetic activity ( Figure 1 c), and with activation in an area consistent with the periaqueductal gray matter (PAG), which mediates heart rate increases under social threat [].

In summary, neuroimaging studies of the learning and extinction of fear in humans reveal evidence of an important differentiation between dorsal ACC and mPFC subregions, which are implicated in threat appraisal and the expression of fear, and ventral ACC and mPFC subregions, which are involved in the inhibition of conditioned fear through extinction.