The pupil-brain system at rest: spontaneous pupil fluctuations as markers of neuromodulatory and network dynamics

This is a preprint and has not been peer reviewed. Data may be preliminary. The pupil-brain system at rest: spontaneous pupil fluctuations as markers of neuromodulatory and network dynamics Abstract Spontaneous pupil fluctuations (SPFs) during rest provide a non-invasive, low-cost index of central arousal dynamics, independent of cognitive task demands. These features position SPFs as promising markers for baseline neurophysiological activity in both basic and translational research. This review synthesizes current evidence on the resting-state pupil-brain system, focusing on its core components: central neuromodulatory circuits and large-scale cortical networks. We first examine the relationship between SPFs and distributed elements of the ascending arousal system, including noradrenergic, cholinergic, and serotonergic nuclei. We then detail SPF coupling with intrinsic functional networks - default mode, salience, and sensorimotor systems - highlighting their role in mediating transitions between internally and externally oriented brain states. Finally, we discuss the spectral and directional properties of pupil-brain interactions, emphasizing analytical approaches suited for assessing causality and outlining implications for clinical and translational applications. Converging evidence from animal and human neuroimaging studies reveals robust spatiotemporal and spectral coupling between SPFs and neural activity across micro- and macro-scales. These findings support a systems-level framework in which SPFs serve as integrative markers linking subcortical neuromodulation with large-scale cortical dynamics. We conclude that SPFs offer a sensitive window into arousal regulation and body-brain integration, with potential utility as biomarkers for neuropsychiatric conditions and altered states of consciousness. Supplementary Material File (manuscript_tl.docx) - Download - 665.80 KB Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Metrics & Citations Metrics Article Usage 219views 88downloads Citations Download citation Tongxin Liu, Sonja Kotz, Antonio Criscuolo, et al. The pupil-brain system at rest: spontaneous pupil fluctuations as markers of neuromodulatory and network dynamics. Authorea. 10 November 2025. DOI: https://doi.org/10.22541/au.176279957.78358538/v1 DOI: https://doi.org/10.22541/au.176279957.78358538/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.