Electroencephalography, pupillometry, and behavioral evidence for locus coeruleus-noradrenaline system related tonic hyperactivity in older adults

Abstract

Neuroimaging studies have shown that age-related dysregulation of the locus coeruleus-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function in vivo, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyper- or hypoactivity, constraining our understanding of underlying mechanisms and hampering the development of targeted preventative interventions. In this study, we acquired electrophysiological, pupillometric, and behavioral measures in a passive and active auditory oddball paradigm to test the hypothesis that cognitively healthy older adults experience tonic LC hyperactivity. We leveraged the LC-NA system's role in arousal regulation and manipulated state arousal and noradrenergic activity using the unpredictable threat of electric shock. Based on older adults' hypothesized tonic LC hyperactivity, we predicted that increased arousal would evoke weaker phasic (stimulus-evoked) noradrenergic responses in older adults compared with young adults. Consistent with this hypothesis, arousal differentially modulated behavioral responses and resting-state alpha power across age groups, and older adults showed smaller pupil dilation responses than young adults. Furthermore, linear mixed models revealed that arousal differentially modulated attentional control to salient but task-irrelevant distractors across age groups, with older adults exhibiting less behavioral slowing and longer P300 latency delays under threat of shock than did young adults. Together these findings provide convergent multi-modal evidence that aging is associated with tonic LC-NA system hyperactivity in humans, with consequences for mechanisms supporting attentional control. This research highlights the utility of non-invasive physiological markers to determine when across the adult lifespan the LC-NA system becomes hyperactive and to identify adults who may be at elevated risk for neurodegenerative progression due to emerging changes in LC-NA system function.

Keywords: Aging; Arousal; Electroencephalography; Locus coeruleus; Pupillometry.