Fear, anxiety, and the extended amygdala- Absence of evidence for strict functional segregation

Abstract

Since the time of Freud, the distinction between fear and anxiety has been a hallmark of influential models of emotion and emotional illness, including the Diagnostic and Statistical Manual of Mental Disorders (DSM) and Research Domain Criteria (RDoC). Fear and anxiety disorders are a leading cause of human misery and morbidity. Existing treatments are inconsistently effective, underscoring the importance of developing accurate models of the underlying neurobiology. Although there is consensus that the extended amygdala (EA) plays a central role in orchestrating responses to threat, the respective contributions of its two major subdivisions-the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST)-remain contentious. To help adjudicate this debate, we performed a harmonized mega-analysis of fMRI data acquired from 295 adults as they completed a well-established threat-anticipation paradigm. Contrary to popular double-dissociation models, results demonstrated that the Ce responds to temporally uncertain threat and the BST responds to certain threat. In direct comparisons, the two regions showed statistically indistinguishable responses, with strong Bayesian evidence of regional equivalence. These observations underscore the need to reformulate conceptual models that posit a strict segregation of temporally certain and uncertain threat processing in the EA.

Keywords: Research Domain Criteria (RDoC); affective neuroscience; bed nucleus of the stria terminalis (BST/BNST); extended amygdala (EA); fear and anxiety.

Figure 1.. Maryland Threat Countdown fMRI Paradigm.

The paradigm takes the form of a 2 (Valence: Threat, Safety) × 2 (Temporal Certainty: Certain, Uncertain) randomized event-related design. Participants were completely informed about the task design and contingencies prior to scanning. On certain-threat trials, participants saw a descending stream of integers (‘countdown’) for 18.75 s. To ensure robust emotion induction, the anticipation epoch always terminated with the presentation of a noxious electric shock, unpleasant photograph, and thematically related audio clip (e.g., scream). Uncertain-threat trials were similar, but the integer stream was randomized and presented for an uncertain and variable duration (8.75–30.00 s; M=18.75 s). Participants knew that something aversive was going to occur, but they had no way of knowing precisely when. Safety trials were similar but terminated with the delivery of emotionally neutral reinforcers (e.g., just-perceptible electrical stimulation). Abbreviation—s, seconds.

Figure 2.. The Maryland Threat Countdown paradigm is a valid probe of human fear and anxiety.

(A) Anticipated threat increases subjective symptoms of distress. Conscious feelings of fear and anxiety were increased during the anticipation of threat compared to safety, and this was particularly evident for temporally uncertain threat (p<0.001). (B) Anticipated threat increases objective signs of arousal. A similar pattern was evident for SCL (p<0.001). Bars depict means, whiskers depict standard errors, and open rings depict individual participants.

Figure 3.. Uncertain- and certain-threat anticipation recruit a common cortico-subcortical network.

Key regions (green arrowheads) show significantly increased activation during the anticipation of both uncertain threat (first column) and certain threat (second column), relative to their respective control conditions (p<0.05, whole-brain FWE corrected). Third column depicts the voxelwise conjunction (logical ‘AND’) of the two thresholded contrasts. Co-localization is evident throughout the network, including the BST and dorsal amygdala (Ce). Fourth column shows the direct contrast of the two threat-anticipation conditions. The MCC, AI/FrO, and to a lesser extent dlPFC/FP, show significantly greater activation during the anticipation of uncertain threat, whereas the BST, dorsal amygdala (Ce), and PAG show negligible discrimination of the two conditions. The dlPFC/FP mean difference was more evident at more rostral planes. For additional details, see Supplementary Tables S1–S6. Purple insets depict magnified views of overlap in the PAG, BST, and Ce. Abbreviations—Ant., Anterior; BST, Bed Nucleus of the Stria Terminalis; dlPFC, Dorsolateral Prefrontal Cortex; FrO, Frontal Operculum; FWE, Familywise Error; PAG, Periaqueductal Gray.

Figure 4.. The human BST and Ce show statistically indistinguishable responses during certain- and uncertain-threat anticipation. (A) Anatomical ROIs.

Probabilistic anatomical ROIs provided statistically unbiased estimates of BST and Ce activation during certain- and uncertain-threat anticipation. Leveraging spatially unsmoothed data, regression coefficients were extracted and averaged across voxels for each combination of ROI, task contrast, and participant. Box plots underscore negligible activation differences during the anticipation of certain-versus-uncertain threat in both the BST (left) and the Ce (right), contrary to double-dissociation models (p>0.16, d<0.09, BF₁₀<0.12). Note: The y-axis scale differs across ROIs. (B) Regional comparison. A standard repeated-measures GLM was used to directly assess potential regional differences in reactivity to certain-versus-uncertain threat. Contrary to the double-dissociation model, the Region × Threat-Certainty interaction was not significant. Boxplot depicts the interaction as a 1-df contrast, that is, the ‘difference of differences.’ Participants were just as likely as not (49.5% vs. 50.5%) to show the hypothesized double dissociation, Z_Sign=0.12, p=0.91. Boxplots depict the median (horizontal lines), interquartile range (boxes), and individual participants (dots) for each contrast. Whiskers indicate 1.5× the interquartile range. Gray lines depict the sign and magnitude of intra-individual mean differences. Inset ring plot depicts the percentage of participants showing the hypothesized dissociation of regional reactivity to threat (BST: Certain < Uncertain Threat; Ce: Certain > Uncertain Threat). Abbreviations—BF, Bayes Factor; BST, bed nucleus of the stria terminalis; Ce, central nucleus of the amygdala; CT, certain-threat anticipation; d, Cohen’s d. fMRI, functional magnetic resonance imaging; FWE, family-wise error; GLM, general linear model; ROI, region-of-interest; UT, uncertain-threat anticipation.