Pupil size is linked to opposite signal fluctuations between cortical BOLD and ventricular CSF

Pupillometry has been used as a biomarker of activity in the Locus Coeruleus (LC), a noradrenergic nucleus crucial for arousal. As the LC has been implicated in modulating cerebrospinal fluid (CSF) flow, here we investigated the associations of pupil size with CSF T2-dependent signal in the ventricles, BOLD signal in cortical and subcortical brain regions (including LC), and peripheral physiology (heart rate and respiration) as a function of arousal. We hypothesized that arousal changes indexed by pupil size would be associated with changes in CSF signal intensity and volume in opposition to brain BOLD signal. Analyses of fMRI data from healthy controls (HCP 7T) showed that changes in pupil size were linked with changes in LC, cortical and subcortical BOLD in opposition to signal changes in the lateral ventricles. CSF signal in the ventricles increased as the activity in LC, thalamus and cortical regions declined concomitant with decreases in pupil size. The coupling between pupil size and LC emerged earlier than for other ascending arousal nuclei and Granger causality analysis corroborated strong LC-pupil coupling. While physiological measures had stronger correlations with each other and with pupil size in the drowsy state, pupil-BOLD and CSF associations were stronger during the vigilant state. The weakened pupil-CSF association in the drowsy state suggests a segregation of central and peripheral signal modulations of CSF during low arousal states. Mental states that promote arousal might be beneficial in neuropsychiatric disorders with glymphatic system impairment and pupillometry could serve as a biomarker to monitor glymphatic function.