JMIR Publications

ABSTRACT

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 reduce 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. The overarching goal is to generate an objective tool of individual early risk prediction, supporting targeted prevention of MHD.

Methods:

LOCUS-MENTAL is a comprehensive research project including different work packages. The centerpiece is an accelerated longitudinal study, in which we recruit a cohort of 300 preschool-aged children (4-6 years of age) and follow them across three assessment waves each one year apart. This will characterize developmental trajectories from 4 to 8 years of age. Psychopathology and childhood adversity will be assessed by established clinical questionnaires and interview measures. Cross-lagged panel models will be applied to the longitudinal data for quantifying causal effects between LC-NE functioning, adversity, and psychopathology. Normative modeling and classification approaches will estimate an individual risk prediction based on pupillometric markers of LC-NE functioning. LC-NE functioning will be assessed by a concise, age-appropriate pupillometry battery of four auditory and visual paradigms. This battery is established in an initial validation phase with a multitrait-multimethod design that combines pupillometry with neurophysiological measures in electroencephalography, behavioral and cognitive measures, and neurocognitive paradigms. Core pupillometry measures are a baseline pupil size (BPS) and a stimulus-evoked pupillary response (SEPR). 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.

Results:

The study was funded in September 2024. Participant enrollment for the validation phase commenced in August 2025. As of December 2025, 48 participants were assessed, with a target of 90 by the end of February 2026. Statistical analysis of the validation phase is planned for March 2026, with results aimed for publication in peer-reviewed journal by the end of 2026. The longitudinal study is scheduled to start in April 2026.

Conclusions:

The LOCUS-MENTAL study will provide critical insights into the role of LC-NE functioning in early childhood as a neurobiological predictor of later psychopathology. By developing and validating a child-friendly, pupillometry-based tool, this research aims to establish an objective method for early risk detection, which is fundamental for advancing targeted prevention of MHDs. Clinical Trial: https://drks.de/search/en/trial/DRKS00035866