An fMRI dysmaturity signature in preterm neonates: Responsiveness of brain areas and its relation to newborn brain development

Abstract

Early brain development is intrinsically dynamic, yet most neonatal resting-state functional magnetic resonance imaging (rs-fMRI) studies rely on static and symmetric measures of functional connectivity. Here, we investigated whether response-based metrics can capture latent dynamical organization of the neonatal brain. We analysed rs-fMRI data from the Developing Human Connectome Project (n = 714). Using a statistical-physics framework grounded in the fluctuation dissipation theorem, we estimated intrinsic pairwise response functions between 46 cortical and subcortical grey matter regions, enabling quantification of regional responsiveness and response duration. Response-based measures differed markedly from conventional functional connectivity and predicted gestational age at birth from a single scan. Preterm infants showed reduced responsiveness and shorter response persistence compared with term born neonates. Importantly, directed analyses revealed a developmental reorganization of driver listener roles across the brain, with preterm infants preserving the regional ordering of the term hierarchy but expressing it at approximately half amplitude. These findings reveal that intrinsic responsiveness captures a previously underappreciated dynamical dimension of neonatal brain organization and provides sensitive markers of neurodevelopmental maturity. Response-based metrics may offer a principled framework for detecting early network dysmaturation following preterm birth. They further indicate that prematurity does not reorganize the directed hierarchy of the neonatal connectome so much as arrest its expansion.