Pupil size reflects activation of subcortical ascending arousal system nuclei during rest

Abstract

Neuromodulatory nuclei that are part of the ascending arousal system (AAS) play a crucial role in regulating cortical state and optimizing task performance. Pupil diameter, under constant luminance conditions, is increasingly used as an index of activity of these AAS nuclei. Indeed, task-based functional imaging studies in humans have begun to provide evidence of stimulus-driven pupil-AAS coupling. However, whether there is such a tight pupil-AAS coupling during rest is not clear. To address this question, we examined simultaneously acquired resting-state fMRI and pupil-size data from 74 participants, focusing on six AAS nuclei: the locus coeruleus, ventral tegmental area, substantia nigra, dorsal and median raphe nuclei, and cholinergic basal forebrain. Activation in all six AAS nuclei was optimally correlated with pupil size at 0–2 s lags, suggesting that spontaneous pupil changes were almost immediately followed by corresponding BOLD-signal changes in the AAS. These results suggest that spontaneous changes in pupil size that occur during states of rest can be used as a noninvasive general index of activity in AAS nuclei. Importantly, the nature of pupil-AAS coupling during rest appears to be vastly different from the relatively slow canonical hemodynamic response function that has been used to characterize task-related pupil-AAS coupling.

A disinhibitory circuit mechanism explains a general principle of peak performance during mid-level arousal

“…Indeed, pupil size and pre-stimulus alpha power are believed to be two sides of the same coin: high arousal states go hand in hand with alpha power suppression and pupil dilation (Aston-Jones & Cohen, 2005; Reimer et al, 2016), and alpha power and pupil diameter appear to be coupled during quiet wakefulness (Montefusco-Siegmund et al, 2022). Yet, there also appear to be dissociations between the effects of pre-stimulus alpha power and pupil-linked arousal on behavior (Lloyd et al, 2023), and there is evidence that suggests that the relationship between alpha power and pupil size is nonlinear (T. Pfeffer et al, 2021; Podvalny et al, 2021). Moreover, a set of studies indicates that pre-stimulus alpha oscillations drive decision bias by modulating neuronal excitability (Iemi et al, 2017, 2022; Kloosterman et al, 2019; Samaha et al, 2020), rather than perceptual sensitivity as we report here.…”

“…These neuromodulators have widespread effects throughout the brain, from controlling global cortical dynamics (e.g., low frequency power (McGinley, Vinck, et al, 2015)) to tuning the gain of sensory processing (McGinley, David, et al, 2015; Reimer et al, 2014; Vinck et al, 2015). Pupil dilation reflects the activity of neuromodulatory nuclei and can therefore be used to non-invasively approximate fluctuations in arousal state (de Gee et al, 2017; Joshi et al, 2016; Lloyd et al, 2023; Murphy, O’Connell, et al, 2014; Reimer et al, 2016; Strauch et al, 2022).…”

Pupil dilation reflects effortful action invigoration in overcoming aversive Pavlovian biases

“…While several studies have reported a correlation between pupil diameter and activity of the locus coeruleus, the main source of noradrenaline in the brain (Joshi & Gold, 2019; Joshi et al, 2016; Murphy, O’Connell, O’Sullivan, Robertson, & Balsters, 2014), this link has recently come under debate (Megemont, McBurney-Lin, & Yang, 2022). Pupil size also correlates with the trial-by-trial BOLD signal activity in other brain stem nuclei, specifically the dopaminergic ventral tegmental area and substantia nigra, at least during rest (Lloyd, de Voogd, Mäki-Marttunen, & Nieuwenhuis, 2023). It might be interesting to consider the possibility that the action-induced modulation of pupil dilation in this study in fact reflect dopaminergic activity (Varazzani et al, 2015; Walton & Bouret, 2018).…”

Functional benefits of cognitively driven pupil‐size changes

“…Conversely, exploitation refers to a behavioral mode characterized by focus on a single task. These behavioral modes correlate with the activity of the locus coeruleus (LC), which in turn is believed to be strongly correlated with pupil size, such that high levels of LC activity are associated with dilated pupils (De Gee et al, 2017; Joshi & Gold, 2020; Liu et al, 2017; Lloyd et al, 2023). Therefore, pupil size, in this context often referred to as pupil‐linked arousal, is often used as a proxy for LC activity to study predictions of the AGT.…”