Pupillometric Markers of Locus Coeruleus–Norepinephrine Activity Are Associated with Internalizing Psychopathology in Adolescents

Abstract Background Stress influences psychopathology across diagnostic categories. Although most stress research has focused on the endocrine stress axis, the locus coeruleus–norepinephrine (LC-NE) system may represent a neurophysiological mechanism of the autonomic stress axis through its regulation of arousal. We therefore examined associations among LC-NE functioning, cortisol, and transdiagnostic psychopathology. Methods Self-reported internalizing and externalizing symptoms were assessed in a clinical sample of 106 adolescents (56 male, 50 female). During auditory and visual oddball paradigms, pupillometry indexed baseline pupil size (BPS) as LC-NE tonic activity and stimulus-evoked pupillary response (SEPR) as LC-NE phasic activity. Endocrine stress was assessed using hair cortisol concentration (HCC) as a retrospective marker and salivary cortisol concentration (SCC) as a current marker. Adjusted linear models tested associations among pupillometry, cortisol measures, and transdiagnostic psychopathology. Results Pupillometry and cortisol measures were uncorrelated but interacted in their associations with psychopathology. Higher BPS, lower HCC, and higher SCC were associated with more internalizing symptoms. The association between BPS and internalizing was stronger at lower SEPR or HCC levels. Only higher SCC was associated with more externalizing symptoms. Combined pupillometry and cortisol measures showed strong performance in classifying clinically relevant internalizing symptoms (n = 42 with T-score > 65; area under the curve [AUC] = .861 [.819, .903]). Conclusion Larger baseline pupil size may reflect hyperarousal indicating increased autonomic activity and serving as a quantitative marker of self-reported internalizing psychopathology. Elevated LC-NE tonic activity may index immediate stress processing distinct from endocrine stress measures and improve differentiation of clinical psychopathology