Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala

Abstract

Neuroticism or negative emotionality (N/NE)—the propensity to experience and express more intense, frequent, or persistent negative affect—is a fundamental dimension of mammalian temperament. Elevated levels of N/NE are associated with a wide range of practically important outcomes, from marital stability and socioeconomic attainment to mental illness and premature death. Despite this, our understanding of the brain bases of N/NE remains far from complete. Converging lines of mechanistic and neuroimaging evidence suggest that N/NE reflects heightened reactivity to genuinely threatening stimuli in the extended amygdala, a circuit encompassing the dorsal amygdala in the region of the central nucleus (Ce) and the lateral division of the neighboring bed nucleus of the stria terminalis (BST), and that this association may be more evident when threat is uncertain. Here, we used a combination of approaches—including a multi-trait, multi-occasion composite of N/NE and neuroimaging assays of threat anticipation and perception—to demonstrate that individuals with a more negative disposition show heightened BST activation during uncertain-threat anticipation. A series of cross-validated, robust regression analyses revealed that N/NE is uniquely predicted by BST reactivity to uncertain-threat anticipation. In contrast, N/NE was unrelated to Ce activation during the anticipation of threat or to extended amygdala activation during the presentation of 'threatening' faces. Follow-up analyses revealed inconsistent evidence of between-task convergence in the BST and Ce, suggesting that threat-anticipation and emotional-face paradigms are not interchangeable probes of extended amygdala function. Collectively, these observations lay the foundation for the kinds of prospective-longitudinal and mechanistic studies that will be necessary to determine causation and, ultimately, to develop improved interventions for extreme N/NE.

A shared threat-anticipation circuit is dynamically engaged at different moments by certain and uncertain threat

“…In fact, as shown in the right column, a minimum-conjunction analysis 50 (Logical 'AND' of the 2 thresholded contrasts) confirmed voxelwise co-localization in each of these key regions. These observations replicate prior work in university and community samples, confirm that our paradigm robustly engages the canonical threat-anticipation circuit, and set the stage for detailed analyses of more complex neural dynamics 32,42,43,45 . Note.…”

“…The MTC is an fMRI-optimized variant of threat assays that have been pharmacologically and psychophysiologically validated in rodents [46][47][48] and humans 25 , maximizing translational relevance. Prior work focused on this and other samples demonstrates that this paradigm robustly increases subjective symptoms of distress and objective signs of arousal, reinforcing its validity as an experimental probe of human fear and anxiety (Supplementary Figure S1) 32,[43][44][45] . Figure 1.…”

“…Skin conductance was continuously acquired throughout. As detailed elsewhere, we used a series of repeated-measures GLMs to confirm that the threat-anticipation paradigm had the intended impact on subjective symptoms of distress and objective signs of arousal 43 . a.…”

“…To address this fundamental question, we used a novel combination of fMRI techniques-including theorydriven hemodynamic modeling, focused region-of-interest (ROI) analyses, and multivoxel brain signature analyses-to interrogate the moment-by-moment dynamics of threat-elicited neural activity and subjective distress in 220 ethnoracially diverse participants. Data were collected using the Maryland Threat Countdown (MTC), a well-established paradigm for manipulating the temporal certainty of threat encounters (Figure 1a) 32,[43][44][45] . The MTC is an fMRI-optimized variant of threat assays that have been pharmacologically and psychophysiologically validated in rodents [46][47][48] and humans 25 , maximizing translational relevance.…”