Neural Mechanisms of Neuroticism: Large-Scale Brain Networks, Developmental Trajectories, and Translational Implications

Neuroticism, a Big Five trait characterized by emotional instability and susceptibility to negative affect, is a robust transdiagnostic predictor for the onset, severity, and persistence of anxiety disorders, major depressive disorder (MDD), and other affective conditions. Recent advances in functional magnetic resonance imaging (fMRI) techniques—including resting-state fMRI, multimodal neuroimaging, and their integration with machine learning—have enabled multi-perspective investigations into the neural substrates of neuroticism. Current research in this field primarily follows three complementary approaches: cross-sectional studies identifying key brain regions for emotional processing and cognitive control (e.g., amygdala (AMG), prefrontal cortex); longitudinal studies capturing neural mechanisms evolution across adolescence, middle age, and old age to elucidate relationships between neuroticism and brain plasticity; and intervention studies exploring plastic pathways for reshaping the neural representations of neuroticism, challenging the classic “trait stability” paradigm. This review synthesizes recent progress in the cognitive neuroscience of neuroticism across these three approaches, proposes a unified emotion-cognition neural model centered on the AMG-prefrontal-default mode network circuit, and outlines a hypothesized lifespan trajectory of Limbic Sensitivity → Regulatory Strain → Prefrontal Decline. While accumulated evidence broadly supports the cross-sectional and interventional pillars of this framework, the lifespan trajectory remains a theoretically informed working model requiring further longitudinal validation. The field still faces critical limitations, including small effect sizes, methodological heterogeneity, and unresolved questions regarding causality and circuit specificity. This review aims to provide a conceptual integration of existing findings, identify key uncertainties, and propose evidence-based future directions. We further link the proposed neural model to clinical phenotypic characteristics of high neuroticism and discuss its implications for targeted neural interventions, thereby advancing our understanding of the biological basis of neuroticism and providing a theoretical framework for prevention and intervention in neuroticism-related affective disorders.