Adaptive pupil-indexed arousal regulation across stress contexts predicts real-world resilience

Stress-related disorders represent a major and persistent global health burden, highlighting the need to identify mechanistic predictors of symptom onset. The arousal system, crucially mediated by locus coeruleus-noradrenergic (LC-NA) activity, is central to the acute stress response and is associated with stress-related psychopathology. Here, we advance these findings, proposing flexibility in arousal regulation to unique demands of environmental contexts as a predictor and potential mechanism of resilience to real-world stress. We followed medical students (N = 102, 73% female, 21-35 years old) with repeated assessments of mental health and stressor exposure for one year during a stressful internship phase. Prior to internship start, participants completed an emotional conflict task under alternating high and low threat-of-shock conditions. We recorded pupil diameter as an established non-invasive readout of the LC-NA arousal system and quantified individual capacity to flexibly adjust pupillary upregulation responses to threat context. Individuals who showed greater upregulation in the high threat context but lower upregulation in the low threat context were more resilient to real-world stress at six and twelve months. These findings identify context-sensitive arousal regulation as a prospective neurobiological marker of real-life resilience and a potential target for preventive intervention.