Making a mountain out of a molehill: On the role of the rostral dorsal anterior cingulate and dorsomedial prefrontal cortex in conscious threat appraisal, catastrophizing, and worrying

Neuroscience and Biobehavioral Reviews 42 (2014) 1–8

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Making a mountain out of a molehill: On the role of the rostral dorsal anterior cingulate and dorsomedial prefrontal cortex in conscious threat appraisal, catastrophizing, and worrying Raffael Kalisch a,b,∗ , Anna M.V. Gerlicher a a Neuroimaging Center (NIC), Focus Program Translational Neuroscience (FTN), Johannes Gutenberg University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany b Institute for Systems Neuroscience, University Medical Center Hamburg-Eppendorf (UKE), Martinistr. 52, 20251 Hamburg, Germany

a r t i c l e

i n f o

Article history: Received 16 September 2013 Received in revised form 20 December 2013 Accepted 3 February 2014 Keywords: Anticipatory anxiety Instructed fear Panic Anxiety sensitivity Evaluation Interoception

a b s t r a c t According to appraisal theories fear and anxiety are elicited by the subjective evaluation of a situation or internal state as threatening. From this perspective anxiety disorders result from maladaptive, exaggerated threat appraisals that over-estimate the threatening consequences of often innocuous stimuli and situations. When these threat over-estimations occur at the level of conscious processing, they are referred to as catastrophizing and worrying. Both are major pathogenic processes in many clinical theories of anxiety. Until recently, little has been known about the neurobiological basis of normal and pathological conscious threat appraisal. Here, we review functional neuroimaging studies which draw a consistent picture of the rostral part of the dorsal anterior cingulate (dACC) and the adjacent dorsomedial prefrontal cortex (dmPFC) as the likely key neural substrate of conscious threat appraisal. Moreover, findings of hyper-activation of the rostral dACC/dmPFC during catastrophizing and worrying emphasize its relevance to aberrant neural processing in anxiety disorders. These insights open a new avenue for improving the prevention and treatment of mental disorders that involve pathological appraisal. © 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of conscious threat appraisal, catastrophizing and worrying in the generation of fear and anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conscious threat appraisal and the rostral dACC/dmPFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Homing in on the rostral dACC/dmPFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Rostral dACC/dmPFC activation to threat does not reflect reinforcement learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Rostral dACC/dmPFC activation to threat does not reflect direct fear response generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Rostral dACC/dmPFC activation is not observed during reward anticipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Threat appraisal in the rostral dACC/dmPFC is not limited to one outcome modality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Rostral dACC/dmPFC activation to threat does not reflect reappraisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Structural and functional connectivity of the rostral dACC/dmPFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Catastrophizing, worrying and the rostral dACC/dmPFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outlook and further questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Note added in proof . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 2 3 3 3 4 4 5 5 5 5 6 6 6 6 6

1. Introduction ∗ Corresponding author at: Neuroimaging Center (NIC), Focus Program Translational Neuroscience (FTN), Johannes Gutenberg University Medical Center, Langenbeckstr. 1, 55131 Mainz, Germany. Tel.: +49 6131 17 4588; fax: +49 6131 17 8346. E-mail address: [email protected] (R. Kalisch). http://dx.doi.org/10.1016/j.neubiorev.2014.02.002 0149-7634/© 2014 Elsevier Ltd. All rights reserved.

Appraisal theories date back to Magda Arnold and her classic work on “Emotion and Personality” (Arnold, 1960). Appraisal theories posit that emotional reactions (understood as an orchestrated multi-level response involving physiological, hormonal, motor,

2

R. Kalisch, A.M.V. Gerlicher / Neuroscience and Biobehavioral Reviews 42 (2014) 1–8

subjective-experiential and cognitive changes) are the result of an evaluation (appraisal) process during which a stimulus or situation is interpreted in terms of its meaning to the organism (Arnold, 1960; Frijda, 1993; Lazarus, 1966; Roseman and Smith, 2001; Scherer, 2001). In other words, the type, quality and extent of an emotional reaction are not determined by simple, fixed stimulusresponse relationships, but by the context-dependent, subjective analysis of the motivational relevance of a stimulus or situation. In this framework, anxiety, fear or panic result from the evaluation of a situation as highly threatening (Lazarus, 1966). Both conscious and unconscious processes are thought to contribute to stimulus appraisal (Leventhal and Scherer, 1987; Robinson, 1998). Unconscious, non-verbal threat appraisal presumably lies at the heart of phylogenetically old threat processing (LeDoux, 1985). Conscious appraisal, however, may be more dominant in unfamiliar and ambiguous situations (Lazarus, 2006) and introduces the possibility of more flexible threat processing, which has become a particularly valuable tool in the treatment of anxiety disorders. Threat appraisals can be maladaptive and can lead to exaggerated fear responses by involving an over-estimation or over-interpretation of a threat. Though not directly referring to appraisal theory, the founding fathers of cognitive therapy have considered erroneous and biased threat appraisal a core feature of all anxiety disorders (Beck and Clark, 1997; Beck et al., 1985). Especially panic disorder is characterized by catastrophic misinterpretations of bodily sensations (Austin and Richards, 2001; Beck et al., 1985; Casey et al., 2004; Clark, 1986). Individuals with panic disorder evaluate innocuous bodily sensations in a catastrophizing manner: an increased pulse rate after climbing some stairs might, for example, be taken as evidence of an upcoming lethal heart attack, the subjectively perceived threat then elicits a further increase in pulse rate, resulting in a vicious cycle that can lead to a full-blown panic attack. Examples of other frequent and typical objects of catastrophizing are the normal feelings of nervousness and concentration problems before an important exam (inducing expectations of failure and performance anxiety), or the ambiguous or critical reactions of an audience and one’s own signs of embarrassment (inducing social-phobic fears). Reiss and McNally (1985) conceptualized the tendency to catastrophize over bodily and mental arousal symptoms as anxiety sensitivity, or “fear of fear”, and introduced a widely used questionnaire tool, the Anxiety Sensitivity Index (ASI), to assess this appraisal style in individuals. Another form of biased threat appraisal, excessive worrying, involves negative estimates of more distant, uncertain and unpredictable dangers. Worry contents might also include external threats such as contracting a disease, losing one’s job, becoming a victim of a crime or more general situations where the threat is not necessarily self-relevant, such as worries about the possibility of war in a different part of the world or the possible impending extinction of human life on Earth due to environmental problems. According to the Diagnostic and Statistical Manual of Mental Disorders, worrying is a core feature of generalized anxiety disorder and also accompanies certain forms of panic disorder. A questionnaire tool that is widely used to assess the individual trait-like tendency to worry, is Meyer et al.’s (1990) Penn State Worry Questionnaire (PSWQ). While exaggerated threat appraisals may well occur at both the unconscious and conscious level, catastrophizing and worrying in the sense used in the clinical literature, requires the conscious perception of the to-be-over-interpreted stimulus and the generation of negative thoughts. Such maladaptive conscious threat appraisal does not only characterize the anxiety disorders but is also a key target in their treatment (Beck et al., 1985; Clark and Beck, 2010). Cognitive therapy tries to change erroneous conscious threat appraisal in favor of more elaborate and adaptive threat appraisal, thereby also diminishing the potential

influence of any underlying maladaptive automatic information processing. Given the theoretical importance of conscious negative threat appraisals in the development, maintenance and therapy of anxiety disorders, defining the neural networks mediating this process is an important step towards a better understanding, prevention and treatment of anxiety disorders. For instance, neural responsivity to threat stimuli in “catastrophizing areas” may predict whether a person is at risk of developing an anxiety disorder as well as the kind of treatment an anxious patient would respond to best. More interestingly, perhaps, is the possibility of targeting aberrant neural processing in such brain areas with the help of neurofeedback or neurostimulation tools, which may complement conventional psychotherapy and increase its efficiency or efficacy. In this review, we focus on the neural underpinnings of conscious threat appraisal and its extreme forms, catastrophizing and worrying. To provide a background, we first briefly discuss empirical findings about the causal role of conscious evaluative processes on normal as well as pathological fear/anxiety. We then review studies on the neural substrates of conscious threat appraisal and discuss recent findings of deviating neural processing during catastrophizing and worrying. Based on these results, we will argue that a relatively well circumscribed brain region situated in the rostral aspects of the dorsal anterior cingulate and the dorsomedial prefrontal cortex (rostral dACC/dmPFC), mediates these processes. We conclude with a list of open questions and suggestions. Addressing them may further advance our understanding of emotional processing under healthy and pathological conditions.

2. The role of conscious threat appraisal, catastrophizing and worrying in the generation of fear and anxiety The central paradigm to study fear or anxiety generation via conscious evaluative processes is ‘instructed fear’, often also termed ‘anticipatory anxiety’ or ‘threat of shock’. In instructed fear experiments, subjects are told that a defined cue (the ‘conditioned stimulus’ or CS in Pavlovian language) might be or will be followed within a certain time window by a harmful event such as a painful electric shock (the outcome or ‘unconditioned’ stimulus, US). In the purest form of instructed fear paradigms, the cue is never actually followed by the outcome, depriving subjects of learning the cue-outcome contingency through experience, as would be the case in Pavlovian conditioning. Yet, subjects typically show clear fear/anxiety reactions that can be measured through selfreport, increases in skin conductance, heart rate or in the startle reflex response (e.g., Cook and Harris, 1937; Funayama et al., 2001; Holtz et al., 2012; Maier et al., 2012; Phelps et al., 2001). In these cases, the conscious knowledge of the cue-outcome contingency and the associated negative appraisal processes are the only plausible sources of the threat response. It has been argued that such learning via instructions is one of the major routes by which fear develops in humans (Olsson and Phelps, 2004). Showing a causal relation between exaggerated conscious appraisal and exaggerated fear is more tricky. Essentially, one has to experimentally induce catastrophizing or worrying thoughts and show corresponding effects in fear responding. One study fulfilling this criterion was recently conducted in healthy subjects reporting trait-like high and low fear of cardiac symptoms (Telch et al., 2010). The authors introduced these subjects to a CO2 inhalation challenge. In the experimental but not the control group the experimenter brought in a cardiac defibrillator briefly before the start of the CO2 inhalation and explained the purpose of its presence as having to do with safety reasons. Subjects with high cardiac-related anxiety reported to appraise the presence of the defibrillator as threatening, in accordance with a successful

R. Kalisch, A.M.V. Gerlicher / Neuroscience and Biobehavioral Reviews 42 (2014) 1–8

induction of catastrophizing. The same subjects also reported increased fear compared to subjects with low cardiac-related anxiety. This trait-specific effect was not observed in the control group. Importantly, increased fear symptoms in the experimental group were limited to subjects with cardiac-specific anxiety and were not observed in subjects with anxiety specifically related to respiratory symptoms or high anxiety sensitivity in general, suggesting that the conscious appraisal of the defibrillator as threatening was crucial for the development of heightened fear. In a different experimental setting, high anxiety sensitivity was related to greater fear in response to body changes induced by a caffeine injection (Telch et al., 1996). Experimental studies that addressed worrying rather than catastrophizing have also observed short-term increases in anxiety and negative emotionality as well as the prolonged maintenance of these emotional states (e.g. Stapinski et al., 2010; for comprehensive reviews see Harvey et al., 2004; Newman et al., 2013). In agreement with the results of controlled laboratory experiments, clinical studies have repeatedly and consistently associated trait measures of exaggerated threat appraisal with panic and other anxiety disorders (Deacon and Abramowitz, 2006; Smits et al., 2008; Taylor et al., 1992). 3. Conscious threat appraisal and the rostral dACC/dmPFC The cingulate cortex has long been assumed to play a central role in processing various emotions (Papez, 1937). Based on its cytoarchitecture, Vogt (2005) suggested a subdivision of the cingulate cortex from anterior to posterior into four regions. He reviewed human neuroimaging studies which examined representations of basic emotions in the cingulate cortex and showed that an area, referred to as the anterior midcingulate cortex (aMCC; Vogt, 2005) or dorsal anterior cingulate cortex (dACC; Etkin et al., 2011), is commonly associated with the emotion of fear. In a more detailed examination of different aspects of fear processing, Etkin and colleagues (Etkin et al., 2011) suggested that the dACC and the adjacent dorsomedial prefrontal cortex (dmPFC) are particularly involved in the appraisal and expression of fear. Other studies have more specifically implicated the dACC and the dmPFC in evaluative judgment and anticipation of emotional stimuli (Blackwood et al., 2004; Cunningham et al., 2004, 2003; Erk et al., 2006; Johnson et al., 2002; Taylor et al., 2003; Vuilleumier et al., 2002). However, these early studies did not explicitly differentiate conscious appraisal from other forms of information processing that also occur during emotional anticipation. They could therefore not exclude the possibility that the observed responses in the dACC/dmPFC may reflect, for instance, unconscious appraisal or the direct generation (execution) of emotional response components (e.g. feelings, motor response tendencies, sympathetic arousal), or also associative learning processes occurring during anticipation experiments. Based on below review of studies addressing these issues, we will try to argue for a further functional subdivision of the dACC/dmPFC into a posterior part and an anterior part, the rostral dACC/dmPFC. The reviewed studies indicate that the rostral but not the posterior dACC/dmPFC is involved in conscious threat appraisal, catastrophizing and worrying. 3.1. Homing in on the rostral dACC/dmPFC To isolate brain responses specific to conscious threat appraisal, Kalisch et al. (2006) employed an instructed fear paradigm in which they additionally modulated the amount of cognitive resources available for conscious threat processing. Subjects in this functional magnetic resonance imaging (fMRI) study were informed that the presence of a certain colored circle, which appeared on the screen for several seconds, signaled a potential shock (threat

3

condition), while the presence of another circle would not (nothreat condition). At the same time, subjects had to conduct an n-back task on a concurrently presented stream of letters. In the high-cognitive-load condition (2-back), subjects had to permanently memorize the recently presented letters in order to press a button whenever the current letter matched the letter presented two screens before. Through this manipulation, the authors tried to capture subjects’ attention and limit cognitive resources available to think about the current situation (threat or no-threat). In the low-cognitive-load control condition (0-back), subjects simply had to report the appearance of each presented letter with a button press. Rostral dACC/dmPFC activation to threat (prominent in the threat/low-cognitive load condition when compared to any no-threat condition) was abolished when subjects no longer had sufficient capacity to consciously appraise the situation (that is, it was reduced in the threat/high-cognitive load relative to the threat/low-cognitive load condition and effectively no longer distinguishable from rostral dACC/dmPFC activity in the no-threat conditions). Fig. 1a depicts the interaction contrast. Importantly, subjective anxiety ratings and heart rate responses to threat were not similarly affected by the cognitive-load manipulation, allowing for dissociating rostral dACC/dmPFC activation from these outcome measures and suggesting that the rostral dACC/dmPFC does not directly mediate the generation of the subjective-experiential (feeling) or physiological response components. In order to assure that the rostral dACC/dmPFC is indeed a reasonable candidate for mediating conscious threat appraisal, Mechias et al. (2010) used a formal meta-analysis of fMRI studies to test whether the rostral dACC/dmPFC shows consistent activation during threat anticipation across instructed fear studies in the literature. This sanity check yielded a positive result (Fig. 1b, white box), thus making way for further pursuit of the hypothesis. No such rostral dACC/dmPFC activation was observed across uninstructed fear (i.e. Pavlovian conditioning) studies, where conscious appraisal may not necessarily be a causal element in fear response generation. Both types of paradigms activated the more posterior part of the dACC/dmPFC, an activation that was interpreted as reflecting common features of instructed and uninstructed fear, such as for example the generation of physiological responses (Etkin et al., 2011; Mechias et al., 2010).

3.2. Rostral dACC/dmPFC activation to threat does not reflect reinforcement learning During most of the studies reviewed in Mechias et al. (2010) subjects occasionally experienced actual cue-outcome (i.e., CS–US) pairings. This might have triggered experiential reinforcement learning and the non-conscious threat appraisal processes that presumably accompany it. Both could be an alternative explanation for rostral dACC/dmPFC activations in those studies. Maier et al. (2012) therefore examined brain responses to pure instructed fear without any further presentation of the outcome (US), again observing prominent rostral dACC/dmPFC activation (Fig. 1c). In an interesting study by Murty et al. (2012), subjects were asked to view images of scenery and encode them for an image-recognition test 24 h later. A cue preceded each image and indicated whether or not subjects were at risk of receiving an electric shock during the future recognition test in the case that they did not successfully recall the respective picture then. Thus, the cues only indicated the possibility of receiving a shock one day later, but no actual shocks were given during the encoding phase. Nevertheless the shock cues elicited greater rostral dACC/dmPFC responses compared to no-shock cues (no figure provided). These findings argue against a contribution of the rostral dACC/dmPFC to experience-based reinforcement learning and further suggest

4

R. Kalisch, A.M.V. Gerlicher / Neuroscience and Biobehavioral Reviews 42 (2014) 1–8

Fig. 1. Rostral dACC/dmPFC activation in relation to conscious threat appraisal and catastrophizing. (a) Kalisch et al. (2006): activation of the rostral dACC/dmPFC in instructed fear (anticipatory anxiety, threat of shock) is abolished when cognitive resources for conscious processing are limited. Montreal Neurological Institute (MNI) coordinates: x, y, z = −8, 38, 28. (b) Meta-analysis by Mechias et al. (2010): the rostral dACC/dmPFC activates consistently across instructed fear studies, MNI: 6, 38, 38 (white box). (c) Maier et al. (2012): the rostral dACC/dmPFC is also active in an instructed fear paradigm where no outcome (US) is presented, MNI: 6, 36, 33. (d) Raczka et al. (2010): during Pavlovian fear conditioning, carriers of a risk genotype for anxiety sensitivity and panic hyper-activate the rostral dACC/dmPFC despite normal skin conductance responses, MNI: 6, 46, 24. (e) Herwig et al. (2007a): the rostral dACC/dmPFC activates more in anticipation of negative compared to positive and neutral outcomes and more during anticipation than during presentation of negative outcomes, MNI: 4, 31, 28. (f) Kalisch et al. (2005): rostral dACC/dmPFC activation in instructed fear is down-regulated by reappraisal, MNI: −4, 46, 28. (g) Robinson et al. (2012): rostral dACC/dmPFC activation to fearful faces shows enhanced coupling with the amygdala during instructed fear, MNI: 10, 34, 40. (h) Holtz et al. (2012): the rostral dACC/dmPFC also activates in anticipation of an interoceptive threat, MNI: 3, 42, 30. (i) Schmälzle et al. (2013): rostral dACC/dmPFC activation during watching a disease-related movie is enhanced in individuals with inflated disease-related risk perception (worrying), MNI: 10, 28, 31 and −2, 38, 10. (j) Peak voxels from studies A–I. We additionally included the peak voxel coordinates reported in the following two studies: (1) Murty et al. (2012): the rostral dACC/dmPFC also activates in anticipation of a potential distal shock, MNI: 18, 32, 12; (2) Paulesu et al. (2010): rostral dACC/dmPFC activity is greater in high-compared to low-worriers after worry-inducing statements, MNI: 0, 44, 22.

that the area may also be involved in the appraisal of distal threats.

3.3. Rostral dACC/dmPFC activation to threat does not reflect direct fear response generation Another potential explanation for rostral dACC/dmPFC activation during threat is the direct generation of fear responses. That is, the rostral dACC/dmPFC could be a down-stream response execution area activated as a result of the threat appraisal process. One relevant response component is the sympathetic arousal that accompanies most forms of fear and anxiety and that is usually indexed via physiological measures such as skin conductance or heart rate. It is well known that more posterior parts of the dACC/dmPFC show consistent positive correlations with such physiological measures (Critchley et al., 2003, 2001; Etkin et al., 2011; Knight et al., 2005; Linnman et al., 2012; Milad et al., 2007; Seifert et al., 2013). These data have been corroborated by lesion and electrical stimulation studies (Critchley et al., 2003; Gentil et al., 2009), raising the question of whether rostral dACC/dmPFC activation to threat could simply reflect recruitment of an extended sympathetic network. Neural responses in the rostral dACC/dmPFC, however, have now repeatedly been shown to be dissociated from physiological fear responses. In the study by Kalisch et al. (2006), high cognitive load diminished threat-related activation specifically in the rostral dACC/dmPFC, but did not attenuate heart rate responses. In a Pavlovian fear conditioning experiment by Raczka et al. (2010), the rostral dACC/dmPFC response to the CS, observable in a group of subjects genetically at risk for anxiety sensitivity and panic (Domschke et al., 2011), was independent of skin conductance responses (Fig. 1d). In another experiment reported in Maier et al. (2012), the slow increases in rostral dACC/dmPFC responses over the course of Pavlovian conditioning and at later fear test followed the observed rapid increase in skin conductance responses with a significant temporal delay, making a direct causal influence of rostral dACC/dmPFC activity on autonomic reactions unlikely (Fig. 1c).

For another relevant fear response component, namely the generation of the feeling of fear/anxiety, a similar dissociation has so far only been observed once (Kalisch et al., 2006). A third component, the activation of general motor response tendencies that is apparent in the fear-related potentiation of the startle reflex, has not been dissociated from rostral dACC/dmPFC activity so far. However, given the anatomical distance and weak connectivity of the rostral dACC/dmPFC and motor preparation and execution areas (Ghashghaei et al., 2007), a motor-based explanation of rostral dACC/dmPFC activity during threat can be considered a remote possibility. Taken together, similarly to reinforcement learning, available data speak against a relevant role of the rostral dACC/dmPFC in fear response execution.

3.4. Rostral dACC/dmPFC activation is not observed during reward anticipation One may argue that the function of the rostral dACC/dmPFC is not limited to the conscious appraisal of threat, but that it serves as a general conscious appraisal area, equally recruited during the anticipation of rewarding or even neutral consequences. A study by Herwig et al. (2007a) directly compared the anticipation of negative to positive and neutral pictures. The authors found greater rostral dACC/dmPFC responses during the anticipation of negative pictures, compared to the anticipation of neutral or positive pictures and to the actual presentation of negative pictures (Fig. 1e). This finding suggests that the rostral dACC/dmPFC specifically responds to the anticipation of threatening and negative stimuli. A result from a recent meta-analysis seems to contradict the valence specificity of rostral dACC/dmPFC responses. Diekhof et al. (2012) investigated the distribution of brain responses to reward anticipation. As one of their results, they presented a significant cluster of voxels located in the rostral dACC/dmPFC (their figure 2, top left panel), which however stemmed from only two peaks (observed in 21 sampled studies; their Fig. 1, top panel, red dots), suggesting inappropriate thresholding and in fact speaking against a major role of the rostral dACC/dmPFC in reward anticipation.

R. Kalisch, A.M.V. Gerlicher / Neuroscience and Biobehavioral Reviews 42 (2014) 1–8

3.5. Threat appraisal in the rostral dACC/dmPFC is not limited to one outcome modality If the rostral dACC/dmPFC indeed mediates the conscious appraisal of threat, then it should activate independently of the sensory modality of the threat. Rostral dACC/dmPFC responses were frequently observed during anticipation of exteroceptive threats such as electric shocks (Kalisch et al., 2006, 2005; Maier et al., 2012; Murty et al., 2012; Robinson et al., 2012) or aversive pictures (Herwig et al., 2007a), as well as during anticipation of an interoceptive threat (i.e. hyperventilation task) (Holtz et al., 2012).

3.6. Rostral dACC/dmPFC activation to threat does not reflect reappraisal Studies on volitional down-regulation of anxiety or other negative emotions via strategies of conscious reappraisal consistently report activity in the posterior dACC/dmPFC during reappraisal (Buhle et al., 2013; Kalisch, 2009). Therefore one may ask whether the rostral dACC/dmPFC activation found during threat anticipation could perhaps also reflect subjects’ attempt to limit their anxiety by trying to take a more positive perspective. Among the few studies investigating the reappraisal of anticipatory emotional responses, three observed no reappraisal-related activation in the rostral dmPFC/dACC (Denny et al., 2013; Herwig et al., 2007b; Paret et al., 2011), while one even observed down-regulation of the rostral dACC/dmPFC (Fig. 1f), accompanied by down-regulation of subjective and physiological anxiety measures (Kalisch et al., 2005). The rostral dACC/dmPFC is thus unlikely to contribute to reappraisal of anticipatory anxiety and may even – in correspondence with its hypothesized role in conscious threat appraisal – be a target of reappraisal processes.

3.7. Structural and functional connectivity of the rostral dACC/dmPFC An area that is involved in the appraisal of threat-related information would be expected to be well connected with other areas of the fear system. The rostral dACC/dmPFC, in particular its cingulate part, has strong reciprocal connections with the adjacent more posterior dACC/dmPFC and connects, directly and indirectly via the more posterior dACC/dmPFC, to the periaqueductal gray, the anterior insula, the amygdala and others (Chiba et al., 2001; Ghashghaei et al., 2007; Grupe and Nitschke, 2013; Stefanacci and Amaral, 2002). On this basis, a recent study investigated the role of functional connectivity between the rostral dACC/dmPFC and the amygdala during threat in humans (Robinson et al., 2012). The authors asked subjects to quickly categorize fearful and happy facial expressions according to their valence while in either threat or no-threat conditions. Functional connectivity between the rostral dACC/dmPFC and the amygdala increased during fearful face processing specifically during threat (as opposed to no-threat) (Fig. 1g), suggesting a potential primary pathway for dorsomedial interactions with the limbic fear circuit. Furthermore, the strength of the positive rostral dACC/dmPFC-amygdala connectivity was positively related to subjects’ trait anxiety. Based on this finding and other reports of positive coupling between the amygdala and rostral dmPFC (Etkin et al., 2011), one may speculate that it is the outcome of threat appraisal processes in the rostral dACC/dmPFC that amplifies amygdala activation to alerting or potentially dangerous stimuli and can thus facilitate an arousal or defensive response. This putative rostral dACC/dmPFC-amygdala pathway may also be a substrate for the vicious cycle of catastrophizing and amplified arousal symptoms observed in panic.

5

4. Catastrophizing, worrying and the rostral dACC/dmPFC Our hypothesis of the rostral dACC/dmPFC as mediator of conscious threat appraisal implies that this area should show hyper-activation during situations that involve exaggerated threat appraisal – such as catastrophizing or worrying. Such a link was suggested by a Pavlovian fear conditioning study reported in Raczka et al. (2010). In this study subjects were intermittently asked to evaluate their experienced stress, fear and tension in response to a CS. In line with exaggerated appraisal of threatening stimuli and/or potentially threatening interoceptive states being encoded in the rostral dACC/dmPFC , subjects who subjectively evaluated their experienced fear reactions as more severe also showed greater rostral dACC/dmPFC response (even when controlling for measured physiological arousal). As it was shown that the T allele of a single nucleotide polymorphism in the neuropeptide S receptor gene NPSR1 is associated with an increased risk of developing panic disorder and with increased anxiety sensitivity (Domschke et al., 2011; Okamura et al., 2007), the authors categorized their subjects into NPSR1 T and non-T allele carriers. Interestingly, during fear acquisition the groups did not exhibit any differences in physiological (SCR) responses to the stimuli. However, the T-carriers evaluated their experienced fear reactions as more severe than non-T carriers, an effect that was reminiscent to the over-interpretation of bodily signals in catastrophizers. T carriers also showed concomitant hyper-activation of the rostral dACC/dmPFC (Fig. 1d). Further evidence was provided by Holtz et al. (2012) who conducted an interoceptive threat task in groups of subjects with high and low anxiety sensitivity. The rostral dACC/dmPFC responses to the instructed anticipation of a hyperventilation task (Fig. 1h) were amplified in the high-anxiety sensitive subjects and were positively correlated with the trait-like tendency to misinterpret and catastrophize about somatic symptoms. The high-anxiety sensitive subjects also reported significantly more panic-related symptoms and subjective fear during anticipation. To examine activity related to worrying, Paulesu et al. (2010) asked subjects pre-selected for high and low worrying, based on their scores on the Penn State Worry Questionnaire (Meyer et al., 1990), to listen to worry-inducing compared to neutral statements and generate thoughts according to the theme of the statements. In the entire sample, both listening and thought generation in the worry condition evoked higher activity in the rostral dACC/dmPFC. High worriers specifically reported prolonged worrying that extended beyond trials and was associated with prolonged hyper-activation of the same area (no figure provided). A different approach was taken by Schmälzle et al. (2013) who presented a TV documentary about the recent H1N1 virus pandemic to individuals with either high or low evaluations of pandemicrelated risks. H1N1 risk perception was assessed via questionnaire and included worry about a H1N1 infection, perceived likelihood of becoming infected and the comparative likelihood of contracting the virus compared to others. Throughout the viewing period, high-compared to low-H1N1 risk-perceiving individuals showed greater inter-subject coupling of neural time courses specifically in the rostral dACC (Fig. 1i), whereas inter-subject time course correlations in other brain areas were not group-specific, suggesting that processes in the rostral dACC reflect inter-individual differences in risk processing. Taken together, although only one of the studies reviewed in this section was able to dissociate threat appraisal from potential concurrent processes like physiological response generation (Raczka et al., 2010) or the preparation of motor activity, they all show rostral dACC/dmPFC hyper-activation in situations of catastrophizing or worrying. The four studies together emphasize a role

6

R. Kalisch, A.M.V. Gerlicher / Neuroscience and Biobehavioral Reviews 42 (2014) 1–8

for the rostral dACC/dmPFC in psychopathological states of fear and anxiety.

5. Outlook and further questions From a cognitive neuroscience point of view, a number of questions remain open. Which aspects of a threatening situation does the rostral dACC/dmPFC deal with? That is, is it concerned with evaluating the probability, magnitude or further consequences of a potential harm? The existing studies have not differentiated between these important dimensions of appraisal. What is the relationship between contingency knowledge (i.e., the ability to explicitly name the association between a cue/CS and an outcome/US, as it is conferred by the experimental instruction in instructed fear experiments) and conscious threat appraisal? Several studies have linked contingency knowledge with hippocampal and lateral prefrontal structures (Bechara et al., 1995; Carter et al., 2006; Clark and Squire, 1998), and one study also found rostral dACC/dmPFC activation in contingency-aware subjects (Tabbert et al., 2006). Can contingency knowledge be conceptualized as a more “cold”, declarative type of knowledge that is supported by a hippocampal-lateral PFC network. And can contingency knowledge thus be differentiated from conscious threat appraisal, which works on this information and adds a valuative or “hot” component? Or are these two processes too intimately linked to be dissociated? Appraisal necessarily works on input information about the structure of the present external or internal environment (such as cues and outcomes), integrating it with past knowledge, current goals and needs and future expectations, to produce an adapted emotional response. The subjective nature of appraisal implies that the outcome of the appraisal process (the emotional response) is open and not determined by the input. Why then is the rostral dACC/dmPFC apparently specialized in the appraisal of threatening information? Does this mean there are upstream primary appraisal instances that mediate a coarse evaluation of the input as signaling a potential threat and funnel this information into the rostral dACC/dmPFC for further processing? Would the same primary appraisal instances activate a different region if the input suggested potential reward? If this were the case, human evolution would have equipped the brain with specialized secondary instances (e.g., the rostral dACC/dmPFC) for the conscious, more elaborate appraisal of already valenced (in this case, negative) information. These questions highlight the need to further examine the functional connectivity of the rostral dACC/dmPFC with other brain regions. Although the studies reviewed above point toward a special role of the rostral dACC/dmPFC in conscious threat appraisal, we believe that its contribution to fear/anxiety can only be understood when considering the distributed network in which it is integrated. A good starting point for a network-oriented investigaton may be a potential function of rostral dACC/dmPFC-amygdala crosstalk for the generation of the vicious ‘panic’ cycle (see Section 3.8). Throughout this review we have not differentiated between the rostral dACC and the rostral dmPFC, even though one may argue that due to their distinct cytoarchitectures the two areas may well provide distinct contributions to threat processing. Fig. 1j could indeed be interpreted as suggesting a localization of conscious appraisal-related activity preferentially in the cingulate cortex. This is a possibility which future work should address. It must however also be taken into consideration that the power of fMRI group studies in resolving small cytoarchitecturally distinct but adjacent areas of the prefrontal cortex is limited, due to the pronounced inter-individual anatomical and functional variability in this part of the brain. Also, Fig. 1j only presents activity peaks, which are

of course surrounded by more widespread activations of extended local networks (see, for example, Fig. 1a–c). At present, therefore, we refrain from proposing any functional subdivision that goes beyond the difference between posterior and anterior dACC/dmPFC with respect to conscious threat appraisal. From a clinical perspective, an interesting question would be whether the catastrophizing- and worrying-related hyperactivations of the rostral dACC/dmPFC can also be observed in patients suffering, for instance, from panic or other anxiety disorders during episodes of catastrophizing. Answering this question may not be trivial, at least not for catastrophizing, for the obvious technical reason that a catastrophizing patient may be difficult to scan. Perhaps the more important question would ask whether the rostral dACC/dmPFC could be a target for interventions aimed at reducing catastrophizing or worrying. For example, patients could be taught to down-regulate the activation of the rostral dACC/dmPFC that is observed during instructed fear in an fMRI experiment – as in the studies reviewed in this paper – with the help of neurofeedback training (Sulzer et al., 2013). It would be hoped that patients would be able to transfer this skill to situations of real-life threat, thereby exerting control over their threat over-estimations and disrupting the vicious cycle of selfenhancing fear. This could be an addition to the therapeutic toolbox – which currently mainly contains cognitive instruments – that would be especially useful for patients who do not respond well to cognitive therapy or have acceptance problems. We expect that further neuroscientific investigation into the issue will be of benefit for both basic emotion research and translational clinical science. Note added in proof During the processing of this manuscript, a study by Servaas et al. (2014) showed activation of the rostral dACC/dmPFC, corresponding to the area highlighted in our Figure 1j, to an experimental worry induction (their Fig. 3). Further, the authors found this activation to correlate with trait worry scores across subjects, in line with the hypothesis presented in this manuscript. Conflict of interest The authors report to have no conflict of interest. Acknowledgements This work was supported by the State of Rhineland-Palatinate (Focus Program Translational Neuroscience) and the Deutsche Forschungsgemeinschaft (DFG grant KA1623/3-1). References Arnold, M.B., 1960. Emotion and Personality. Columbia University Press. Austin, D.W., Richards, J.C., 2001. The catastrophic misinterpretation model of panic disorder. Behav. Res. Ther. 39, 1277–1291. Bechara, A., Tranel, D., Damasio, H., Adolphs, R., Rockland, C., Damasio, A.R., 1995. Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 269, 1115– 1118. Beck, A.T., Clark, D.A., 1997. An information processing model of anxiety: automatic and strategic processes. Behav. Res. Ther. 35, 49–58. Beck, A.T., Emery, G., Greenberg, R.L., 1985. Anxiety Disorders and Phobias: A Cognitive Perspective. Basic Books, Cambridge, MA. Blackwood, N.J., Bentall, R.P., Ffytche, D.H., Simmons, A., Murray, R.M., Howard, R.J., 2004. Persecutory delusions and the determination of self-relevance: an fMRI investigation. Psychol. Med. 34, 591–596. Buhle, J.T., Silvers, J.A., Wager, T.D., Lopez, R., Onyemekwu, C., Kober, H., Weber, J., Ochsner, K.N., 2013. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cereb. Cortex, 1991.

R. Kalisch, A.M.V. Gerlicher / Neuroscience and Biobehavioral Reviews 42 (2014) 1–8 Carter, R.M., O’Doherty, J.P., Seymour, B., Koch, C., Dolan, R.J., 2006. Contingency awareness in human aversive conditioning involves the middle frontal gyrus. Neuroimage 29, 1007–1012. Casey, L.M., Oei, T.P.S., Newcombe, P.A., 2004. An integrated cognitive model of panic disorder: the role of positive and negative cognitions. Clin. Psychol. Rev. 24, 529–555. Chiba, T., Kayahara, T., Nakano, K., 2001. Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata. Brain Res. 888, 83–101. Clark, D.A., Beck, A.T., 2010. Cognitive theory and therapy of anxiety and depression: convergence with neurobiological findings. Trends Cogn. Sci. 14, 418–424. Clark, D.M., 1986. A cognitive approach to panic. Behav. Res. Ther. 24, 461–470. Clark, R.E., Squire, L.R., 1998. Classical conditioning and brain systems: the role of awareness. Science 280, 77–81. Cook, S.W., Harris, R.E., 1937. The verbal conditioning of the galvanic skin reflex. J. Exp. Psychol. 21, 202–210. Critchley, H.D., Mathias, C.J., Dolan, R.J., 2001. Neural activity in the human brain relating to uncertainty and arousal during anticipation. Neuron 29, 537–545. Critchley, H.D., Mathias, C.J., Josephs, O., O’Doherty, J., Zanini, S., Dewar, B.-K., Cipolotti, L., Shallice, T., Dolan, R.J., 2003. Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain J. Neurol. 126, 2139–2152. Cunningham, W.A., Johnson, M.K., Gatenby, J.C., Gore, J.C., Banaji, M.R., 2003. Neural components of social evaluation. J. Pers. Soc. Psychol. 85, 639–649. Cunningham, W.A., Raye, C.L., Johnson, M.K., 2004. Implicit and explicit evaluation: FMRI correlates of valence, emotional intensity, and control in the processing of attitudes. J. Cogn. Neurosci. 16, 1717–1729. Deacon, B., Abramowitz, J., 2006. Anxiety sensitivity and its dimensions across the anxiety disorders. J. Anxiety Disord. 20, 837–857. Denny, B.T., Ochsner, K.N., Weber, J., Wager, T.D., 2013. Anticipatory brain activity predicts the success or failure of subsequent emotion regulation. Soc. Cogn. Affect. Neurosci., http://dx.doi.org/10.1093/scan/nss148. Diekhof, E.K., Kaps, L., Falkai, P., Gruber, O., 2012. The role of the human ventral striatum and the medial orbitofrontal cortex in the representation of reward magnitude – an activation likelihood estimation meta-analysis of neuroimaging studies of passive reward expectancy and outcome processing. Neuropsychologia 50, 1252–1266. Domschke, K., Reif, A., Weber, H., Richter, J., Hohoff, C., Ohrmann, P., Pedersen, A., Bauer, J., Suslow, T., Kugel, H., Heindel, W., Baumann, C., Klauke, B., Jacob, C., Maier, W., Fritze, J., Bandelow, B., Krakowitzky, P., Rothermundt, M., Erhardt, A., Binder, E.B., Holsboer, F., Gerlach, A.L., Kircher, T., Lang, T., Alpers, G.W., Ströhle, A., Fehm, L., Gloster, A.T., Wittchen, H.-U., Arolt, V., Pauli, P., Hamm, A., Deckert, J., 2011. Neuropeptide S receptor gene – converging evidence for a role in panic disorder. Mol. Psychiatry 16, 938–948. Erk, S., Abler, B., Walter, H., 2006. Cognitive modulation of emotion anticipation. Eur. J. Neurosci. 24, 1227–1236. Etkin, A., Egner, T., Kalisch, R., 2011. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn. Sci. 15, 85–93. Frijda, N.H., 1993. The place of appraisal in emotion. Cogn. Emot. 7, 357–387. Funayama, E.S., Grillon, C., Davis, M., Phelps, E.A., 2001. A double dissociation in the affective modulation of startle in humans: effects of unilateral temporal lobectomy. J. Cogn. Neurosci. 13, 721–729. Gentil, A.F., Eskandar, E.N., Marci, C.D., Evans, K.C., Dougherty, D.D., 2009. Physiological responses to brain stimulation during limbic surgery: further evidence of anterior cingulate modulation of autonomic arousal. Biol. Psychiatry 66, 695–701. Ghashghaei, H.T., Hilgetag, C.C., Barbas, H., 2007. Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala. Neuroimage 34, 905–923. Grupe, D.W., Nitschke, J.B., 2013. Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat. Rev. Neurosci. 14, 488–501. Harvey, A.G., Watkins, E., Mansell, W., Shafran, R., 2004. Cognitive Behavioural Processes Across Psychological Disorders: A Transdiagnostic Approach to Research and Treatment. Oxford University Press, Oxford/New York. Herwig, U., Abler, B., Walter, H., Erk, S., 2007a. Expecting unpleasant stimuli—an fMRI study. Psychiatry Res. 154, 1–12. Herwig, U., Baumgartner, T., Kaffenberger, T., Brühl, A., Kottlow, M., Schreiter-Gasser, U., Abler, B., Jäncke, L., Rufer, M., 2007b. Modulation of anticipatory emotion and perception processing by cognitive control. Neuroimage 37, 652–662. Holtz, K., Pané-Farré, C.A., Wendt, J., Lotze, M., Hamm, A.O., 2012. Brain activation during anticipation of interoceptive threat. Neuroimage 61, 857–865. Johnson, S.C., Baxter, L.C., Wilder, L.S., Pipe, J.G., Heiserman, J.E., Prigatano, G.P., 2002. Neural correlates of self-reflection. Brain J. Neurol. 125, 1808–1814. Kalisch, R., 2009. The functional neuroanatomy of reappraisal: time matters. Neurosci. Biobehav. Rev. 33, 1215–1226. Kalisch, R., Wiech, K., Critchley, H.D., Dolan, R.J., 2006. Levels of appraisal: a medial prefrontal role in high-level appraisal of emotional material. Neuroimage 30, 1458–1466. Kalisch, R., Wiech, K., Critchley, H.D., Seymour, B., O’Doherty, J.P., Oakley, D.A., Allen, P., Dolan, R.J., 2005. Anxiety reduction through detachment: subjective, physiological, and neural effects. J. Cogn. Neurosci. 17, 874–883. Knight, D.C., Nguyen, H.T., Bandettini, P.A., 2005. The role of the human amygdala in the production of conditioned fear responses. Neuroimage 26, 1193–1200. Lazarus, R.S., 1966. Psychological Stress and the Coping Process. McGraw-Hill.

7

Lazarus, R.S., 2006. Stress and Emotion: A New Synthesis. Springer Publishing Company, New York, NY, US. LeDoux, J.E., 1985. The Emotional Brain. Touchstone, New York, NY, US. Leventhal, H., Scherer, K., 1987. The relationship of emotion to cognition: a functional approach to a semantic controversy. Cogn. Emot. 1, 3–28. Linnman, C., Zeidan, M.A., Pitman, R.K., Milad, M.R., 2012. Resting cerebral metabolism correlates with skin conductance and functional brain activation during fear conditioning. Biol. Psychol. 89, 450–459. Maier, S., Szalkowski, A., Kamphausen, S., Perlov, E., Feige, B., Blechert, J., Philipsen, A., van Elst, L.T., Kalisch, R., Tüscher, O., 2012. Clarifying the role of the rostral dmPFC/dACC in fear/anxiety: learning, appraisal or expression? PLoS ONE 7, e50120. Mechias, M.-L., Etkin, A., Kalisch, R., 2010. A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. Neuroimage 49, 1760–1768. Meyer, T.J., Miller, M.L., Metzger, R.L., Borkovec, T.D., 1990. Development and validation of the Penn State Worry Questionnaire. Behav. Res. Ther. 28, 487–495. Milad, M.R., Quirk, G.J., Pitman, R.K., Orr, S.P., Fischl, B., Rauch, S.L., 2007. A role for the human dorsal anterior cingulate cortex in fear expression. Biol. Psychiatry 62, 1191–1194. Murty, V.P., Labar, K.S., Adcock, R.A., 2012. Threat of punishment motivates memory encoding via amygdala, not midbrain, interactions with the medial temporal lobe. J. Neurosci. Off. J. Soc. Neurosci. 32, 8969–8976. Newman, M.G., Llera, S.J., Erickson, T.M., Przeworski, A., Castonguay, L.G., 2013. Worry and generalized anxiety disorder: a review and theoretical synthesis of evidence on nature, etiology, mechanisms, and treatment. Annu. Rev. Clin. Psychol. 9, 275–297. Okamura, N., Hashimoto, K., Iyo, M., Shimizu, E., Dempfle, A., Friedel, S., Reinscheid, R.K., 2007. Gender-specific association of a functional coding polymorphism in the Neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 1444–1448. Olsson, A., Phelps, E.A., 2004. Learned fear of “unseen” faces after Pavlovian, observational, and instructed fear. Psychol. Sci. 15, 822–828. Papez, J., 1937. A proposed mechanism of emotion. Arch. Neurol. Psychiatry 38, 725–743. Paret, C., Brenninkmeyer, J., Meyer, B., Yuen, K.S.L., Gartmann, N., Mechias, M.-L., Kalisch, R., 2011. A test for the implementation-maintenance model of reappraisal. Front. Psychol. 2, 216. Paulesu, E., Sambugaro, E., Torti, T., Danelli, L., Ferri, F., Scialfa, G., Sberna, M., Ruggiero, G.M., Bottini, G., Sassaroli, S., 2010. Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study. Psychol. Med. 40, 117–124. Phelps, E.A., O’Connor, K.J., Gatenby, J.C., Gore, J.C., Grillon, C., Davis, M., 2001. Activation of the left amygdala to a cognitive representation of fear. Nat. Neurosci. 4, 437–441. Raczka, K.A., Gartmann, N., Mechias, M.-L., Reif, A., Büchel, C., Deckert, J., Kalisch, R., 2010. A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing. Mol. Psychiatry 15, 1067–1074. Reiss, S., McNally, R.J., 1985. Expectancy model of fear. In: Reiss, S., Bootzin, R.R. (Eds.), Theoretical Issues in Behaviour Therapy. Academic Press, New York, NY, US, pp. 107–121. Robinson, M.D., 1998. Running from William James’ Bear: a review of preattentive mechanisms and their contributions to emotional experience. Cogn. Emot. 12, 667–696. Robinson, O.J., Charney, D.R., Overstreet, C., Vytal, K., Grillon, C., 2012. The adaptive threat bias in anxiety: amygdala-dorsomedial prefrontal cortex coupling and aversive amplification. Neuroimage 60, 523–529. Roseman, I.J., Smith, C.A., 2001. Appraisal theory: overview, assumptions, varieties, controversies. In: Scherer, K.R., Schorr, A., Johnstone, T. (Eds.), Appraisal Processes in Emotion: Theory, Methods, Research, Series in Affective Science. Oxford University Press, New York, NY, US, pp. 3–19. Servaas, M.N., Riese, H., Ormel, J., Aleman, A., 2014. The neural correlates of worry in association with individual differences in neuroticism. Hum. Brain Mapp., http://dx.doi.org/10.1002/hbm.22476, Epub ahead of print. Scherer, K.R., 2001. Appraisal considered as a process of multilevel sequential checking. In: Scherer, K.R., Schorr, A., Johnstone, T. (Eds.), Appraisal Processes in Emotion: Theory, Methods, Research. Oxford University Press, New York, NY, US, pp. 92–120. Schmälzle, R., Häcker, F., Renner, B., Honey, C.J., Schupp, H.T., 2013. Neural correlates of risk perception during real-life risk communication. J. Neurosci. Off. J. Soc. Neurosci. 33, 10340–10347. Seifert, F., Schuberth, N., De Col, R., Peltz, E., Nickel, F.T., Maihöfner, C., 2013. Brain activity during sympathetic response in anticipation and experience of pain. Hum. Brain Mapp. 34, 1768–1782. Smits, J.A.J., Berry, A.C., Tart, C.D., Powers, M.B., 2008. The efficacy of cognitivebehavioral interventions for reducing anxiety sensitivity: a meta-analytic review. Behav. Res. Ther. 46, 1047–1054. Stapinski, L.A., Abbott, M.J., Rapee, R.M., 2010. Evaluating the cognitive avoidance model of generalised anxiety disorder: impact of worry on threat appraisal, perceived control and anxious arousal. Behav. Res. Ther. 48, 1032–1040. Stefanacci, L., Amaral, D.G., 2002. Some observations on cortical inputs to the macaque monkey amygdala: an anterograde tracing study. J. Comp. Neurol. 451, 301–323. Sulzer, J., Haller, S., Scharnowski, F., Weiskopf, N., Birbaumer, N., Blefari, M.L., Bruehl, A.B., Cohen, L.G., DeCharms, R.C., Gassert, R., Goebel, R., Herwig, U., LaConte, S.,

8

R. Kalisch, A.M.V. Gerlicher / Neuroscience and Biobehavioral Reviews 42 (2014) 1–8

Linden, D., Luft, A., Seifritz, E., Sitaram, R., 2013. Real-time fMRI neurofeedback: progress and challenges. Neuroimage 76, 386–399. Tabbert, K., Stark, R., Kirsch, P., Vaitl, D., 2006. Dissociation of neural responses and skin conductance reactions during fear conditioning with and without awareness of stimulus contingencies. Neuroimage 32, 761–770. Taylor, S., Koch, W.J., McNally, R.J., 1992. How does anxiety sensitivity vary across the anxiety disorders? J. Anxiety Disord. 6, 249–259. Taylor, S.F., Phan, K.L., Decker, L.R., Liberzon, I., 2003. Subjective rating of emotionally salient stimuli modulates neural activity. Neuroimage 18, 650–659. Telch, M.J., Silverman, A., Schmidt, N., 1996. Effects of anxiety sensitivity and perceived control on emotional responding to caffeine challenge. J. Anxiety Disord. 10, 21–35.

Telch, M.J., Smits, J.A.J., Brown, M., Dement, M., Powers, M.B., Lee, H., Pai, A., 2010. Effects of threat context and cardiac sensitivity on fear responding to a 35% CO2 challenge: a test of the context-sensitivity panic vulnerability model. J. Behav. Ther. Exp. Psychiatry 41, 365–372. Vogt, B.A., 2005. Pain and emotion interactions in subregions of the cingulate gyrus. Nat. Rev. Neurosci. 6, 533–544. Vuilleumier, P., Armony, J.L., Clarke, K., Husain, M., Driver, J., Dolan, R.J., 2002. Neural response to emotional faces with and without awareness: event-related fMRI in a parietal patient with visual extinction and spatial neglect. Neuropsychologia 40, 2156–2166.