Elsevier

NeuroImage

Volume 55, Issue 1, 1 March 2011, Pages 389-400
NeuroImage

Phasic and sustained fear in humans elicits distinct patterns of brain activity

https://doi.org/10.1016/j.neuroimage.2010.11.057Get rights and content

Abstract

Aversive events are typically more debilitating when they occur unpredictably than predictably. Studies in humans and animals indicate that predictable and unpredictable aversive events can induce phasic and sustained fear, respectively. Research in rodents suggests that anatomically related but distinct neural circuits may mediate phasic and sustained fear. We explored this issue in humans by examining threat predictability in three virtual reality contexts, one in which electric shocks were predictably signaled by a cue, a second in which shocks occurred unpredictably but never paired with a cue, and a third in which no shocks were delivered. Evidence of threat-induced phasic and sustained fear was presented using fear ratings and skin conductance. Utilizing recent advances in functional magnetic resonance imaging (fMRI), we were able to conduct whole-brain fMRI at relatively high spatial resolution and still have enough sensitivity to detect transient and sustained signal changes in the basal forebrain. We found that both predictable and unpredictable threat evoked transient activity in the dorsal amygdala, but that only unpredictable threat produced sustained activity in a forebrain region corresponding to the bed nucleus of the stria terminalis complex. Consistent with animal models hypothesizing a role for the cortex in generating sustained fear, sustained signal increases to unpredictable threat were also found in anterior insula and a frontoparietal cortical network associated with hypervigilance. In addition, unpredictable threat led to transient activity in the ventral amygdala–hippocampal area and pregenual anterior cingulate cortex, as well as transient activation and subsequent deactivation of subgenual anterior cingulate cortex, limbic structures that have been implicated in the regulation of emotional behavior and stress responses. In line with basic findings in rodents, these results provide evidence that phasic and sustained fear in humans may manifest similar signs of distress, but appear to be associated with different patterns of neural activity in the human basal forebrain.

Research Highlights

► Predictable threats evoke phasic fear and transient activity in dorsal amygdala. ► Unpredictable threats induce sustained fear and prolonged activity in BNST complex. ► Unpredictable threats lead to sustained insula and frontoparietal activation.

Introduction

In humans and animals, unpredictable aversive events produce debilitating behavioral, cognitive, and somatic effects similar to those found in anxiety and mood disorders (Grillon et al., 2004, Mineka and Kihlstrom, 1978). These effects are usually not found when the same aversive events or threats are predictable (Grillon et al., 2004, Mineka and Hendersen, 1985), suggesting that unpredictable threats are generally more harmful. Studies in humans and rats indicate that predictable threats typically induce phasic fear, a short-lasting apprehension concerning imminent threat, and that unpredictable threats generally induce sustained fear, a longer-lasting apprehension elicited by potential or temporally uncertain threat (Davis et al., 2010b). Rodent data suggest that highly related but partially distinct functional neuroanatomical networks may underlie phasic and sustained fear (Davis et al., 2010b). It is currently unclear whether similar mechanisms support the expression of phasic and sustained fear in humans. The present study investigated this issue using a threat predictability procedure adapted for high-resolution fMRI and virtual reality presentation.

Predictable and unpredictable threats induce similar signs of fear but elicit distinct behavioral and neural responses. In humans and animals, a brief, discrete cue that predictably signals an imminent threat evokes a rapid apprehensive state (phasic fear) that diminishes quickly once the threat is terminated, and triggers active defensive responses such as attack, escape, and physiological reactivity (Fanselow, 1994, Grillon, 2008). In contrast, a diffuse cue that signals a temporally unpredictable threat (e.g., a hazardous environment) elicits a longer-lasting anxiety-like state (sustained fear) associated with passive defensive behaviors such as hypervigilance, avoidance, and quiescence (Blanchard and Blanchard, 2008, Grillon, 2008). Rodent data suggest that phasic fear responses rely on the central nucleus of the amygdala (CeA), which in humans is located in the dorsal part of the amygdala (Amunts et al., 2005), whereas sustained fear responses are dependent on the bed nucleus of the stria terminalis (BNST), which is located in the ventromedial basal forebrain and receives input from the CeA and the more ventrally located basolateral amygdala complex (BLC) (Walker and Davis, 2008). Together with neuronal groups alongside the stria terminalis (supracapsular BNST) and those located beneath the globus pallidus (sublenticular BNST), the CeA and BNST form a neuronal continuum known as the extended amygdala (Alheid and Heimer, 1988, Heimer et al., 1999). Because the CeA and BNST project to the same neural mediators of fear symptoms, each of these components of the extended amygdala are capable of generating defensive responses (Davis and Whalen, 2001).

Consistent with animal research centrally implicating the amygdala in cued fear conditioning and extinction, neuroimaging studies in humans have likewise implicated the amygdala in fear acquisition and extinction (Buchel et al., 1998, Labar et al., 1998, Milad et al., 2007, Phelps et al., 2004). To identify the neural mechanisms that underlie fear expression, however, it may be more advantageous to examine instructed fear in humans rather than fear conditioning (Davis et al., 2010b). In studies of instructed fear, subjects are verbally informed beforehand of the likelihood of experiencing an aversive event when encountering a stimulus, rather than having to learn this probability through direct experience. For example, Phelps et al. (2001) instructed individuals that they were at risk of receiving an electric shock when they encountered a briefly presented cue of one color (threat cue) but not another color (safe cue). Though no shocks were ever administered, the threat cue evoked enhanced arousal and fear as indexed by skin conductance, and relative to the safe cue, produced a rapid and short-lasting activation in left dorsal amygdala. In a similar study but one using [O-15]H20 positron emission tomography and the delivery of occasional shocks to enhance procedural credibility, Hasler et al. (2007) found that a visual threat cue increased cerebral blood flow in the left amygdala relative to a comparable safe cue. Studies of instructed fear that have examined neural activity underlying both anticipation of and responses to briefly presented aversive pictures have also revealed dorsal amygdala activation (Mackiewicz et al., 2006, Nitschke et al., 2006), provided that the aversive events are predictably signaled (Sarinopoulos et al., 2010). These previous findings support the hypothesis that a neural circuit within the dorsal amygdala may mediate phasic fear in humans.

While many neuroimaging studies in humans have investigated the role of the amygdala in phasic fear, few have examined the specific role of the BNST in sustained fear (Straube et al., 2007). However, Somerville et al. (2010) recently examined the role of the BNST in anxious-related vigilance. In the present study, we investigated whether the BNST was associated with a sustained state of anxiety. Based on the above pre-clinical research in animals and previous neuroimaging studies, we hypothesized that in humans a cue signaling imminent shock would elicit phasic fear responses and transient activity in the dorsal amygdala, whereas the threat of temporally unpredictable shock would produce sustained fear responses and sustained activity in the BNST. Based in part on anterograde and retrograde tract-tracing studies showing that anterior insular cortex projects heavily to the extended amygdala (McDonald et al., 1999), animal models of sustained fear posit that cortical inputs from the insula may also underlie sustained fear, possibly mediating cognitive components of anxious apprehension (Davis et al., 2010b). Therefore, we further hypothesized that the threat of unpredictable shock would generate sustained activity in anterior insula, an area that also has strong projections to medial prefrontal cortical regions associated with the regulation of emotions and visceral reactions (Price and Drevets, 2010).

We tested these predictions using a well-validated instructed threat procedure (Davis et al., 2010b, Grillon et al., 2004), and neuroimaging methods that assured good signal detection of transient cue- and context-related responses, as well as sustained context-related responses in the basal forebrain. Because of partial volume effects from cerebrospinal fluid (CSF) in the cerebral ventricles, it is methodologically challenging to use BOLD fMRI contrast to examine relatively small structures in the basal forebrain. Standard fMRI voxel volumes (e.g., 3.8 × 3.8 × 4.0 mm3) are typically not small enough to decrease partial volume effects nor do they provide the spatial resolution required to detect fMRI signal changes from small brain regions. Imaging at a higher spatial resolution can decrease partial volume effects but can come at the cost of a reduced MRI signal-to-noise ratio (SNR) (Edelstein et al., 1986). Therefore, to boost SNR, we employed a multi-element surface coil array and conducted parallel imaging fMRI (Bodurka et al., 2004). This allowed us to conduct whole-brain fMRI at roughly 4 times higher spatial resolution (1.7 × 1.7 × 3.5 mm3) and still have enough sensitivity to detect BOLD signal changes (Bodurka et al., 2007). Moreover, combining parallel imaging and voxel volume reduction provides the added benefit of reducing susceptibility-related signal dropout from different tissue interfaces (Bellgowan et al., 2006).

Section snippets

Subjects

Eighteen healthy volunteers (10 males, mean age = 24.7 years, SD = 3.7 years) participated in the study and gave written informed consent approved by the NIMH Human Investigation Review Board. Inclusion criteria included 1) no past or current psychiatric disorders as per Structured Clinical Interview for DSM-IV; 2) no medical condition that interfered with the study objectives; and 3) no use of illicit drugs or psychoactive medications as per urine screen. All subjects in the study exhibited minimal

Results

Fear ratings (ANX) and skin conductance responses (SCRs) to contexts and cues differed depending on shock predictability [Stimulus Type × Condition interaction, ANX: F(1.6, 27.5) = 38.13, P < 0.001; Fig. 2A; SCR: F(1.6, 28.5) = 17.74, P < 0.001; Fig. 2B]. Paired t-tests revealed that the predictable cue (Pcue) [ANX: mean (SEM) 7.3 (0.3); SCR: 0.45 (0.06)] was more anxiogenic than the predictable context (Pcxt) [ANX: 4.3 (0.5); t17 = 6.0, P < 0.001; SCR: 0.26 (0.04); t17 = 5.2, P < 0.001] as well as the

Discussion

The present study compared neural processing of phasic and sustained fear in humans as induced by predictable and unpredictable threat, respectively. Behaviorally, predictable and unpredictable threat evoked pronounced emotional reactions as indicated by subjective fear ratings and skin conductance. In addition, aversive events invoked greater sustained anxiety when they occurred unpredictably than predictably. Using high-resolution fMRI, we found that predictable and unpredictable threat

Acknowledgments

This study was supported by the Intramural Research Program of the National Institute of Mental Health.

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