Locus-Coeruleus Norepinephrine Functioning as a Predictor of Childhood Mental Health (LOCUS-MENTAL): Protocol for a Longitudinal Study.

Background: Mental health disorders (MHDs) remain a leading cause of the global burden of diseases. Early identification of neurobiological mechanisms mediating a risk for MHDs is key to reducing a lifetime burden. Recent findings emphasize the locus coeruleus-norepinephrine (LC-NE) system as a neuromodulator of arousal translating acute stress responses into neuronal excitability. We propose that individual differences in LC-NE functioning can explain a differential susceptibility to psychological adversity, which mediates the development of transdiagnostic psychopathology in early childhood. Objective: The primary objective of LOCUS-MENTAL is to assess LC-NE functioning in preschoolers as a predictor of later psychopathology. This will be applied to generate an objective tool of individual early risk prediction, supporting targeted prevention of MHD. Methods: LOCUS-MENTAL includes 4 work packages. The centerpiece is an accelerated longitudinal study, in which a cohort of 300 preschool-aged children (aged 4-6 years) will be recruited and followed up across 3 assessment waves, each one year apart. This will characterize developmental trajectories from 4 to 8 years of age. The primary outcome is the prediction of transdiagnostic psychopathology by pupillometry-derived LC-NE functioning. Transdiagnostic psychopathology is assessed by the Child Behavior Checklist (CBCL), while LC-NE functioning is assessed with pupillometry that includes core metrics of baseline pupil size (BPS) and stimulus-evoked pupillary response (SEPR). Cross-lagged panel models will be applied to the longitudinal data for quantifying causal effects between LC-NE functioning, childhood adversity, and psychopathology. Normative modeling and classification approaches will estimate an individual risk prediction based on pupillometric metrics of LC-NE functioning. The pupillometric battery has 4 passive auditory and visual paradigms. This battery will be validated with a multitrait-multimethod design that combines pupillometry with neurophysiological measures in electroencephalography, behavioral and cognitive measures, and neurocognitive paradigms. The study was approved by the Ethics Committee of the Faculty of Medicine at Goethe University Hospital (2024-2160). Written informed consent will be obtained from caregivers and verbal assent by the children. Results: The study was funded in September 2024. Participant enrollment for the validation phase commenced in August 2025. As of February 2026, 82 participants were assessed, with a target of reaching 90 by the end of February 2026. Statistical analysis of the validation phase is planned for March 2026, with results aimed for publication in a peer-reviewed journal by the end of 2026. The longitudinal study is scheduled to start in April 2026 with completion in March 2029. Conclusions: The LOCUS-MENTAL study will establish whether LC-NE functioning provides a validated biomarker for detecting early psychopathology. The associated pupillometry provides a feasible and scalable test for identifying high-risk developmental trajectories in preschool children, which can be translated to clinical practice. The resulting risk assessment tool could facilitate a shift toward objective screening for mental health risks that enables targeted prevention with evidence-based treatment before diagnosis onset. This could prevent sequential comorbidity and reduce the lifetime burden of MHDs.