Fear is only as deep as the mind allows: A coordinate-based meta-analysis of neuroimaging studies on the regulation of negative affect
Research highlights
► Coordinate-based meta-analysis revealed a domain-general affect regulation mechanism. ► VMPFC controlled perceived aversiveness during extinction, placebo and reappraisal. ► Deactivation of the amygdala accompanied reduction of negative affect in all domains. ► Placebo and cognitive reappraisal engaged further regions to diminish negative affect.
Introduction
During the last decade there have been a growing number of neuroimaging studies that dealt with the neural underpinnings of the regulation of negative affect in general and of experienced fear in particular. Using different experimental approaches researchers have thereby tried to reveal the neural mechanisms through which humans can modulate the perception of threatening and unpleasant events. It has been demonstrated that the degree of negative affect elicited by aversive stimuli and their predictors can be significantly reduced by misleading advance information (like in placebo experiments; e.g., de Jong et al., 1996, Diekhof et al., 2011, Wager et al., 2004b), by prior experience of significant changes in the original stimulus–outcome associations (like in fear extinction experiments; e.g., Kalisch et al., 2006a), or by a voluntary cognitive reappraisal of these events (like in experiments involving a cognitive down-regulation of negative emotion; e.g., Ochsner et al., 2004). This raises the question of whether these different experimental domains share a common neural mechanism for the control of perceived aversiveness and negative affect.
In fact, from a process-oriented perspective the three experimental domains of fear extinction, placebo control and voluntary cognitive emotion regulation are quite heterogeneous and show only partial overlap in the involved cognitive operations. During fear extinction conditioned fear responses are extinguished following non-reinforced exposure to the feared conditioned stimulus (CS). Thereafter, two memories exist in the brain: the original, weakened association between the CS and the unconditioned aversive stimulus (UCS), and a new CS/no-UCS association, which leads to a decline of conditioned responses like anticipatory anxiety and negative arousal (Myers and Davis, 2007, Quirk et al., 2006). Conversely, a reduction of the subjectively experienced aversiveness of painful or otherwise unpleasant stimuli through placebo interventions (i.e., a sham treatment or a misleading expectation) is commonly achieved through two processes that supposedly act in concert. On the one hand, placebo treatments produce a soothing effect because the recipient expects them to do so. This means that simply by expecting a less aversive stimulus than factually presented, stimulus perception is altered (e.g., pain is reduced), which ultimately changes the associated physiological responses and also reduces the degree of experienced negative affect (Kirsch, 1985). On the other hand, through repeated association with an US (e.g., the effect of the active drug), objects, places, people, and procedures can become CSs, capable of eliciting an effect, which is similar or related to the real drug effect. Thus the placebo acts as a CS that leads to a placebo effect, which can be understood as a conditioned response (Steward-Williams and Podd, 2004). In that way, placebo interventions can alter the subjective experience of an aversive event through a combination of placebo expectancy and placebo conditioning (e.g., Nitschke et al., 2006, Wager et al., 2004b, Watson et al., 2009). Finally, voluntary cognitive emotion regulation operates on an event that – like in placebo studies – maintains its objective aversiveness (e.g., a photograph of a mutilated dead body). However, through cognitive reappraisal the meaning of the aversive event can be altered which over time significantly changes the associated physiological responses and reduces the degree of subjectively experienced negative affect. Common reappraisal strategies employ emotional detachment, reinterpretation, mental imagery or cognitive reexamination to control negative physiological responses like the degree of experienced fear (see Ochsner and Gross, 2005). The cognitive operations involved in these cognitive regulation strategies are by far more sophisticated than those underlying implicit placebo conditioning or extinction recall, and further need to be voluntary engaged to cope with the aversive event.
In line with the differences between the three experimental domains, neuroimaging studies have identified various brain regions implicated in the down-regulation of negative affective responses. Studies of fear extinction have put forward an important role for the ventromedial prefrontal cortex (VMPFC) and adjacent rostral anterior cingulate cortex (rACC) (Finger et al., 2008, Milad et al., 2007, Soliman et al., 2010) as well as for the hippocampus (Kalisch et al., 2006a, Milad et al., 2007) in extinction recall and for the basolateral nucleus of the amygdala in the early phases of extinction learning (Quirk and Beer, 2006, Quirk et al., 2006). Together these regions may control physiological fear responses in down-stream areas like the central nucleus of the amygdala (Milad et al., 2006). Moreover, placebo effects were found to be mediated by several prefrontal regions that reduced the threatening potential and the perceived aversiveness of the painful or otherwise aversive stimuli. Among these were the VMPFC with the adjacent rACC and the subgenual ACC (sgACC) (e.g., Bingel et al., 2006, Eippert et al., 2009, Diekhof et al., 2011, Petrovic et al., 2005, Sarinopoulos et al., 2006), the lateral orbitofrontal cortex (OFC) (e.g., Diekhof et al., 2011, Sarinopoulos et al., 2006, Wager et al., 2004b), and parts of the dorsolateral prefrontal cortex (e.g., Wager et al., 2004b). Increased activation in these brain regions was found to accompany reduced activation in the amygdala and sensory cortices (e.g., Petrovic et al., 2005, Sarinopoulos et al., 2006), which significantly changed the evaluation of the events. Other studies, which particularly tested placebo-induced responses in neurotransmission, found increased opioidergic and dopaminergic transmission in the same control regions during the experience of placebo analgesia (e.g., Scott et al., 2008, Zubieta et al., 2005). Finally, studies in the domain of cognitive emotion regulation put forward an important role for higher-order brain regions, mainly located in the dorsolateral and dorsomedial prefrontal cortex as well as in the lateral OFC (see Ochsner and Gross, 2005 for review). Increased activation in these prefrontal regions was accompanied by a significant reduction of the perceived aversiveness of the presented photographs and an (indirect) modulation of negative affective responses in the amygdala and associated brain regions (e.g., Banks et al., 2007, Delgado et al., 2008). A fraction of these affect regulation studies also found evidence for an involvement of the VMPFC in the voluntary regulation of negative affect (e.g., Delgado et al., 2008, Urry et al., 2006), although less consistently than in the other two experimental domains. Collectively, these diverse findings leave open the question whether there is a central regulation system that controls negative affective responses in the human brain.
In view of the heterogeneity of the neuroimaging findings it is interesting to investigate whether a common neural mechanism underlies the human ability to alter the subjective perception of aversive stimuli regardless of the type of regulation strategy employed. To identify those regions in the human brain that are consistently implicated in the control of negative affective responses independent of paradigm-specific cognitive operations and sensory modality (most extinction and placebo studies used painful stimuli, while reappraisal studies predominantly presented aversive pictures to induce negative affective responses; see Tables A1–3), we performed a coordinate-based quantitative meta-analysis. Through an integration of the results of the entirety of relevant neuroimaging studies, coordinate-based quantitative meta-analysis offers a powerful tool to assess convergence of findings from different experimental domains (Eickhoff et al., 2009, Laird et al., 2005a, Turkeltaub et al., 2002). In that way, it further overcomes the drawbacks of study-specific characteristics like differences in experimental design, stimulus modality, data analysis technique or imprecise use of anatomical labels, which complicate the generalizability of the results from individual studies (Caspers et al., 2010). Our hypothesis was that brain regions, which are activated irrespective of the above described differences between the experimental domains of fear extinction, placebo control and cognitive emotion regulation, can be regarded as belonging to a universal affect regulatory brain system. The identification of the common neural substrate of diminishing negative affect is not only important for a procedural understanding of affect regulation, but also holds further implications for our understanding of how mental processes may drive physiological responses in general and how they can bias sensory perception.
Section snippets
Material and methods
We performed a coordinate-based quantitative meta-analysis using the activation likelihood estimation (ALE) method (Eickhoff et al., 2009, Laird et al., 2005a, Turkeltaub et al., 2002 available at http://brainmap.org/ale/index.html). This analysis assessed the voxelwise correspondence of neuroimaging results from three types of affect regulation experiments (i.e., (1.) fear extinction, (2.) placebo control, and (3.) cognitive emotion regulation). In particular, we wanted to examine the
Results
The Pubmed search and subsequent application of the inclusion criteria yielded a total of 49 relevant articles published within the last decade. Ten of these articles assessed hyperactivations underlying the process of fear extinction yielding 55 foci inside the brain mask used by GingerALE 2.0.4 (see Table A1). Another 14 studies assessed the neural mechanisms mediating placebo effects. These studies yielded 122 coordinates within the borders of the brain mask (see Table A2). Finally, 25
Discussion
In the present study, we used coordinate-based ALE meta-analysis to determine brain areas central to the (voluntary) down-regulation of negative affect and to the control of perceived aversiveness. We were particularly interested in control regions and therefore only coordinates from studies reporting hyperactivations related to diminishing negative affect were included in three independent meta-analyses. The three independent meta-analyses of hyperactivations revealed that a region in the
Conclusion
Taken together, the present meta-analytic findings underscore the important role of the human VMPFC in the control of perceived aversiveness and negative affect. By demonstrating a domain-general response in the VMPFC that was accompanied by a significant down-regulation of activation in the amygdala, our data suggest that this prefrontal brain region may be an important controller of subjectively perceived aversiveness that modulates affective responses in the human brain regardless of task
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