Phasic and sustained fear in humans elicits distinct patterns of brain activity
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.
References (64)
- et al.
New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata
Neuroscience
(1988) - et al.
Improved BOLD detection in the medial temporal region using parallel imaging and voxel volume reduction
Neuroimage
(2006) - et al.
Mapping the MRI voxel volume in which thermal noise matches physiological noise—implications for fMRI
Neuroimage
(2007) - et al.
Brain systems mediating aversive conditioning: an event-related fMRI study
Neuron
(1998) - et al.
Predictability modulates the affective and sensory-discriminative neural processing of pain
Neuroimage
(2006) AFNI: software for analysis and visualization of functional magnetic resonance neuroimages
Comput. Biomed. Res.
(1996)- et al.
Topography of projections from amygdala to bed nuclei of the stria terminalis
Brain Res. Brain Res. Rev.
(2001) - et al.
Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study
Neuron
(1998) - et al.
A meta-analysis of instructed fear studies: implications for conscious appraisal of threat
Neuroimage
(2010) - et al.
Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert
Biol. Psychiatry
(2007)
Functional neuroanatomy of aversion and its anticipation
Neuroimage
Self-referential processing in our brain—a meta-analysis of imaging studies on the self
Neuroimage
Responses of amygdaloid central nucleus neurons to stimulation of the insular cortex in awake rabbits
Neuroscience
Extinction learning in humans: role of the amygdala and vmPFC
Neuron
A new method for improving functional-to-structural MRI alignment using local Pearson correlation
Neuroimage
Human bed nucleus of the stria terminalis indexes hypervigilant threat
Biol. Psychiatry
Waiting for spiders: brain activation during anticipatory anxiety in spider phobics
Neuroimage
The amygdala and appraisal processes: stimulus and response complexity as an organizing factor
Brain Res. Brain Res. Rev.
Contextual fear conditioning in humans: cortical–hippocampal and amygdala contributions
J. Neurosci.
Anatomical organization of the primate amygdaloid complex
Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps
Anat. Embryol. (Berl)
Defensive behaviors, fear, and anxiety
Scalable multichannel MRI data acquisition system
Magn. Reson. Med.
Electrodermal activity
A different recruitment of the lateral and basolateral amygdala promotes contextual or elemental conditioned association in Pavlovian fear conditioning
Learn. Mem.
The identification of multiple outliers (with discussion)
J. Am. Stat. Assoc.
The amygdala: vigilance and emotion
Mol. Psychiatry
Regional response differences across the human amygdaloid complex during social conditioning
Cereb. Cortex
Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety
Neuropsychopharmacology
The subgenual anterior cingulate cortex in mood disorders
CNS Spectr.
The human brain: surface, three-dimensional sectional anatomy with mri, and blood supply
The intrinsic signal-to-noise ratio in NMR imaging
Magn. Reson. Med.
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