Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis

Abstract

ABSTRACTNeuroticism/Negative Emotionality (N/NE)—the tendency to experience and express more frequent, intense, or persistent negative affect—is a fundamental dimension of childhood temperament and adult personality, with profound consequences for health, wealth, and wellbeing. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment and divorce to mental illness and premature death. Yet our understanding of the underlying neurobiology remains surprisingly speculative. Work in animals suggests that N/NE reflects heightened reactivity to uncertain threat in the central extended amygdala (EAc)—including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST)—but the relevance of these discoveries to the complexities of the human brain and temperament have remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to understand the relevance of the EAc to variation in N/NE in an ethnoracially diverse sample selectively recruited to capture a broad spectrum of N/NE. Cross-validated, robust regression analyses demonstrated that trait-like variation in N/NE is uniquely associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat. In contrast, N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or EAc reactivity to ‘threat-related’ faces. While the BST is often associated with anxiety, analyses showed that heightened BST reactivity to uncertain threat is more broadly associated with the ‘internalizing’ facets of N/NE, including depression. Implicit in much of the neuroimaging literature is the assumption that different threat paradigms are statistically interchangeable probes of individual differences in neural function, yet our analyses revealed negligible evidence of convergence between popular threat-anticipation and threat-perception (emotional faces) tasks in the EAc. These observations provide a framework for conceptualizing emotional traits and the development of emotional disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for informing mechanistic research in humans and animals.