Pupil diameter covaries with BOLD activity in human locus coeruleus

Abstract

The locus coeruleus-noradrenergic (LC-NA) neuromodulatory system has been implicated in a broad array of cognitive processes, yet scope for investigating this system's function in humans is currently limited by an absence of reliable non-invasive measures of LC activity. Although pupil diameter has been employed as a proxy measure of LC activity in numerous studies, empirical evidence for a relationship between the two is lacking. In the present study, we sought to rigorously probe the relationship between pupil diameter and BOLD activity localized to the human LC. Simultaneous pupillometry and fMRI revealed a relationship between continuous pupil diameter and BOLD activity in a dorsal pontine cluster overlapping with the LC, as localized via neuromelanin-sensitive structural imaging and an LC atlas. This relationship was present both at rest and during performance of a two-stimulus oddball task, with and without spatial smoothing of the fMRI data, and survived retrospective image correction for physiological noise. Furthermore, the spatial extent of this pupil/LC relationship guided a volume-of-interest analysis in which we provide the first demonstration in humans of a fundamental characteristic of animal LC activity: phasic modulation by oddball stimulus relevance. Taken together, these findings highlight the potential for utilizing pupil diameter to achieve a more comprehensive understanding of the role of the LC-NA system in human cognition.

Pupil dilation during recognition memory: Isolating unexpected recognition from judgment uncertainty

“…Critically, electrical activity in the monkey LC is closely associated with the moment to moment dilation of the pupil (Rajkowski, Kubiak, & Aston-Jones, 1993), and concurrently measured pupil diameter covaries with LC activation during both rest and the oddball decision task in human fMRI studies (Murphy, O'Connell, O'Sullivan, Robertson, & Balsters, 2014). Given the close association between the LC activity and the PD response in uncertainty.…”

How emotion context modulates unconscious goal activation during motor force exertion

“…Activity of the PAG, a key midbrain structure involved in emotional processing and defensive motor behaviours (Blakemore et al, 2016;Satpute et al, 2013), was also modulated by subjective arousal. We note that our result might additionally reflect activity in the adjacent locus coereleus, as this structure is also implicated in mediating arousal (Murphy et al, 2014) and energizing behaviour (Varazzani et al, 2015). However, this remains speculative as our imaging parameters limit the ability to differentiate PAG activity from activity of surrounding brainstem nuclei (Satpute et al, 2013).…”

Mechanisms underlying memory enhancement in humans

“…Converging evidence from fMRI and pupilometry measures -an indirect index of LC activation (Alnaes et al, 2014;Gilzenrat, Cohen, Rajkowski, & Aston-Jones, 2003;Gilzenrat et al, 2010;Jepma & Nieuwenhuis, 2011;Joshi et al, 2016;Murphy et al, 2014Murphy et al, , 2011bRajkowski, Kubiak, & Aston-Jones, 1993)-demonstrate a noradrenergic drive in the episodic memory enhancement observed during voluntary movement execution. Furthermore, this LC activation is functionally coupled with a memory target area, parahippocampal gyrus, suggesting a framework in which noradrenaline release triggered by voluntary movements engages memory target areas to promote episodic memory encoding.…”

“…In general they found that LC activity was higher just preceding pupil dilations compared with constrictions, implying that the pupil changes do not cause changes in LC activation, rather they reflect underlying changes in The first study in humans that detailed the interrelationship between performance dynamics on a widely used attentional task and pupil diameter as an indirect index of LC-NE system activity was performed by (Murphy et al, 2011). In a new set of experiments, the same authors have recently demonstrated a positive correlation between continuous pupil diameter and BOLD activity in a dorsal pontine cluster overlapping with the LC by simultaneously recording pupilometry and fMRI both at rest and during performance of a two-stimulus oddball task (Murphy, O'Connell, O'Sullivan, Robertson, & Balsters, 2014). LC was localized via both neuromelaninsensitive structural imaging (Shibata et al, 2006) and a previously published LC atlas (Keren, Lozar, Harris, Morgan, & Eckert, 2009).…”

“…To provide a second, independent index of LC activity during Go-induced encoding enhancement, we next performed the same Go/NoGo memory paradigm while recording pupil diameter responses (Exp 6). Pupil diameter has been shown to be a reliable, indirect index of LC activation, positively correlating with LC firing rates in non-human primates (Gilzenrat et al, 2003;Gilzenrat et al, 2010;Jepma & Nieuwenhuis, 2011;Joshi et al, 2016;Rajkowski, Kubiak, & Aston-Jones, 1993) and with BOLD activity in human LC (Alnaes et al, 2014;Gilzenrat et al, 2010;Murphy et al, 2014;Murphy, Robertson, Balsters, & O'connell, 2011b) (see Chapter 2.2.1). We therefore expected that the pupil-derived index of LC activation would relate to memory performance and movement in the same way as that observed with fMRI scanning (Figure 19).…”