Contributions of the Central Extended Amygdala to Fear and Anxiety

Abstract

It is widely thought that phasic and sustained responses to threat reflect dissociable circuits centered on the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST), the two major subdivisions of the central extended amygdala. Early versions of this hypothesis remain highly influential and have been incorporated into the National Institute of Mental Health Research Research Domain Criteria framework. However, new observations encourage a different perspective. Anatomical studies show that the Ce and BST form a tightly interconnected unit, where different kinds of threat-relevant information can be integrated and used to assemble states of fear and anxiety. Imaging studies in humans and monkeys show that the Ce and BST exhibit similar functional profiles. Both regions are sensitive to a range of aversive challenges, including uncertain or temporally remote threat; both covary with concurrent signs and symptoms of fear and anxiety; both show phasic responses to short-lived threat; and both show heightened activity during sustained exposure to diffusely threatening contexts. Mechanistic studies demonstrate that both regions can control the expression of fear and anxiety during sustained exposure to diffuse threat. These observations compel a reconsideration of the central extended amygdala's contributions to fear and anxiety and its role in neuropsychiatric disease.

Keywords: affective neuroscience; fMRI; fear and anxiety; mood and anxiety disorders; neuroimaging; nonhuman primates.

Figure 1.

Primate central extended amygdala. Simplified schematic of key central extended amygdala inputs and outputs in humans and other primates. The central extended amygdala encompasses the central (Ce) nucleus of the amygdala, which lies in the dorsal amygdala, and the bed nucleus of the stria terminalis (BST), which wraps around the anterior commissure. As shown by the translucent white arrow at the center of the figure, much of the sensory (yellow), contextual (blue), and regulatory (green) inputs to the central extended amygdala are indirect (i.e., polysynaptic), and often first pass through adjacent amygdala nuclei before arriving at the Ce or BST. In primates, projections linking the Ce with the BST are predominantly from the Ce to the BST. The Ce and BST are both poised to orchestrate or trigger momentary states of fear and anxiety via projections to downstream effector regions (orange; for additional detail, see Fig. 2). Portions of this figure were adapted with permission from the human brain atlas of Mai et al. (2007). BL, Basolateral; BM, basomedial; Ce, central; La, lateral; Me, medial nuclei of the amygdala.

Figure 2.

Early model and inconsistent human imaging evidence. a, Early model emphasizing strict functional segregation in the extended amygdala. In earlier work, Davis, Walker, and their colleagues noted that the Ce and BST send similar projections to the brainstem and hypothalamic regions that proximally mediate particular elements of fear and anxiety (e.g., tachycardia, startle potentiation). Based on the available evidence, they hypothesized that the Ce and BST reflected dissociable circuits that differentially processed specific types of threat. Although Davis and colleagues subsequently reformulated their hypothesis (Davis et al., 2010), the basic tenets of the 1998 model continue to permeate the literature and NIMH RDoC initiative. This figure is a redrawing of the schematic shown in Davis (1998) and incorporates elements adapted with permission from the human brain atlas of Mai et al. (2007). b, Examples of human imaging data inconsistent with the early model of Davis and colleagues. Left, Sustained/long-term activation in the Ce in response to a virtual reality context (30 s) paired with unpredictable electric shocks. Middle, Ce and BST both show phasic/short-term activation in response to an explicit, unconditioned threat (4 s video clips of an approaching tarantula). Right, BST activation in response to explicit, conditioned and unconditioned threats. Figure represents the minimum conjunction (logical “AND”) of thresholded maps (p < 0.005) derived from two imaging meta-analyses: one focused on activation associated with the experience of experimentally induced negative affect (Wager et al., 2008) and the other focused on activation elicited by aversive Pavlovian conditioned stimuli (Etkin and Wager, 2007). The two meta-analytic maps are freely available at http://www.columbia.edu/cu/psychology/tor/MetaAnalysis.htm. Portions of the bottom are adapted with permission from Mobbs et al., (2010), Andreatta et al. (2015), and Fox et al. (2015a).

Figure 3.

Assessing fear- and anxiety-relevant brain function in monkeys and humans. a, BST and Ce are related to sustained threat in young monkeys. In our nonhuman primate model, we simultaneously assess behavior, neuroendocrine activity, and brain metabolism. At the beginning of the session, the monkey receives an injection of a radiotracer, 18-fluorodeoxyglucose (FDG) and is placed alone in a testing cage. Paralleling behavioral paradigms (e.g., “strange situation”) used to assess fear and anxiety in children, in some experiments an unfamiliar human experimenter (“intruder”) enters the room and stands motionless outside the cage while presenting his or her profile to the subject. In contrast to other forms of stress, such as direct threats, the adaptive response in this context is to inhibit vocalizations and freeze, decreasing the likelihood of detection by the intruder. Immediately following the intruder challenge, plasma is collected for quantifying neuroendocrine activity (e.g., cortisol), and subjects are anesthetized and positioned in a stereotactic device within the high-resolution, small-bore PET scanner. The PET scanner then measures the amount of FDG uptake during the preceding 30 min behavioral paradigm; regions that were more metabolically active during the behavioral challenge take up more radiolabeled glucose. Metabolism in the Ce and BST is associated with heightened signs of fear and anxiety (fewer vocalizations, more freezing, and elevated levels of the stress-sensitive hormone cortisol) during prolonged (30 min) exposure to the human intruder's profile (n = 592) (Fox et al., 2015b). b, Automated meta-analysis of “fear” and “anxiety” studies in humans reveals BST and Ce activation. Figure represents the minimum conjunction (logical “AND”) of thresholded forward inference maps (q < 0.01) automatically generated by Neurosynth (Yarkoni et al., 2011) for studies tagged with the keyword “fear” (298 studies) or “anxiety” (312 studies). c, Sustained BST activation during the uncertain anticipation of aversive images. Somerville et al. (2013) presented standardized negative or neutral images (3 s) (Lang et al., 1998) in blocks (118 s) where the timing of presentations was either certain or uncertain. Analyses demonstrated that sustained activation in the BST closely tracked mean differences in self-reported fear and anxiety across the four blocked conditions (i.e., uncertain-negative > certain-negative > uncertain-neutral > certain-neutral). Portions of this figure were adapted with permission from Somerville et al. (2013) and Fox et al. (2015b).