Functional Coupling of the Locus Coeruleus Is Linked to Successful Cognitive Control

Abstract

The locus coeruleus (LC) is a brainstem structure that sends widespread efferent projections throughout the mammalian brain. The LC constitutes the major source of noradrenaline (NE), a modulatory neurotransmitter that is crucial for fundamental brain functions such as arousal, attention, and cognitive control. This role of the LC-NE is traditionally not believed to reflect functional influences on the frontoparietal network or the striatum, but recent advances in chemogenetic manipulations of the rodent brain have challenged this notion. However, demonstrations of LC-NE functional connectivity with these areas in the human brain are surprisingly sparse. Here, we close this gap. Using an established emotional stroop task, we directly compared trials requiring response conflict control with trials that did not require this, but were matched for visual stimulus properties, response modality, and controlled for pupil dilation differences across both trial types. We found that LC-NE functional coupling with the parietal cortex and regions of the striatum is substantially enhanced during trials requiring response conflict control. Crucially, the strength of this functional coupling was directly related to individual reaction time differences incurred by conflict resolution. Our data concur with recent rodent findings and highlight the importance of converging evidence between human and nonhuman neurophysiology to further understand the neural systems supporting adaptive and maladaptive behavior in health and disease.

The impact of age and Alzheimer’s disease on locus coeruleus mediated neuromodulation of neural circuits and goal-directed behavior

“…1C. Pupillometry as a non-invasive measure of LC activation Non-luminance mediated changes in pupil size are relatively easy to measure non-invasively and have been found to covary with a range of behavioral, cognitive and autonomic factors and with neural activity in many parts of the brain including some of the major neuromodulatory systems [Jepma and Nieuwenhuis, 2011 Grueschow et al, 2022]. For this review, I will focus on relationships between changes in pupil size and activation of the LC-NE system.…”

Linking tonic and phasic pupil responses to P300 amplitude in an emotional face‐word Stroop task

“…Using an emotional face-word Stroop task (Etkin et al, 2006), it has been demonstrated that the LC-NE system is involved in emotional conflict resolution (Grueschow et al, 2022), and more importantly, pupillary responses in this task have been linked to the LC-NE system (Grueschow et al, 2020(Grueschow et al, , 2021, revealing larger task-evoked pupil dilation in the incongruent condition compared to the congruent condition. Consistent with previous research (Grueschow et al, 2020(Grueschow et al, , 2021, we replicated these findings in a cohort of Asian participants using culturally distinct face-word stimuli, showing larger pupil dilation in the incongruent condition compared to the congruent condition.…”

“…It is also important to note that the LC-NE system interconnects with various areas of the brain in the context of pupil modulations (Joshi & Gold, 2020;Strauch et al, 2022). For instance, recent evidence suggests that the functional coupling between the LC-NE system and frontoparietal regions is crucial in predicting individual differences in cognitive control during an emotional face-word Stroop task (Grueschow et al, 2020(Grueschow et al, , 2021(Grueschow et al, , 2022. These together suggest that caution should be exercised when interpreting changes in pupil size at constant luminance as an exclusive measure of the activity of the LC-NE system, and considerations on the complex relationship between pupillary responses and the LC-NE system under different task conditions are needed to examine the LC-P3 hypothesis.…”

“…Moreover, evidence from mice has demonstrated pupil dilation correlates with LC activity, it can only predict a subset of LC spiking activity levels (Megemont et al, 2022;Yang et al, 2021). Moreover, given that other neural circuits also exert significant control over pupil size (Ebitz & Moore, 2017;Joshi & Gold, 2020;Lehmann & Corneil, 2016;Strauch et al, 2022;Wang et al, 2012;Wang & Munoz, 2023), these circuits could potentially interact with the LC-NE system (e.g., Grueschow et al, 2022) and contribute to the observed results. Therefore, caution is needed when interpreting our results as direct evidence linking P300 to the LC-NE system.…”

“…The emotional face‐word Stroop task has been employed to assess the effects of emotional response conflict (Etkin et al., 2006). Evidence has demonstrated that the locus coeruleus (LC), which modulates the arousal system by releasing norepinephrine (NE) throughout most of the brain (referred to hereafter as LC‐NE), plays a significant role in cognitive control (Aston‐Jones & Cohen, 2005; Breton‐Provencher & Sur, 2019; Carter et al., 2010; Grueschow et al., 2022; Mather & Harley, 2016; Poe et al., 2020). Furthermore, the dysfunction of the LC‐NE system is often associated with various clinical symptoms (Betts et al., 2019; Dahl et al., 2022; Gong et al., 2021; Joshi, 2023; Mather et al., 2020; Morris et al., 2020).…”