Pupil Size as a Window on Neural Substrates of Cognition

Joshi, Siddhartha; Gold, Joshua I.

doi:10.1016/j.tics.2020.03.005

Cited by 446 publications

(510 citation statements)

References 186 publications

(216 reference statements)

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“…As described above, decades of research have shown that eye metrics are related to task performance in a variety of contexts [8][9][10][11][12][13]. Heightened levels of arousal have been associated with a large pupil.…”

Section: Discussionmentioning

confidence: 99%

“…A large body of work has shown that arousal is associated with changes in the action of the eyes, be it when they are relatively stable or when they move. For example, increases in arousal are typically accompanied by increases in pupil size and saccade velocity, and concomitant decreases in microsaccade rate and reaction time [8][9][10][11][12][13][30][31][32][33][38][39][40][41]. Given that arousal is a domain-general phenomenon, one might expect a similar pattern to emerge on different behavioral tasks.…”

Section: Correlations Between the Eye Metrics Over Timementioning

confidence: 99%

“…Much has been learned about cognitive processes, and their development, from studying the action of the eyes [1][2][3][4][5][6][7]. In addition, a large body of research has shown that properties related to the eyes can be used to index global brain states such as arousal, motivation and cognitive effort [8][9][10][11][12][13]. The action of the eyes can be considered broadly in two contexts -the action of the pupil when the eyes are relatively stable, and the action of the eyes when they move, be it voluntarily, in response to novel objects in the visual field, or involuntarily during periods of steady fixation.…”

Section: Introductionmentioning

confidence: 99%

“…However, the pupil does not merely reflect accommodation. Instead, the size of the pupil is controlled by a balance between parasympathetic and sympathetic pathways that reflect both light-driven accommodation and central modulation [12]. Several studies have shown that pupil size is associated with arousal [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…Instead, the size of the pupil is controlled by a balance between parasympathetic and sympathetic pathways that reflect both light-driven accommodation and central modulation [12]. Several studies have shown that pupil size is associated with arousal [9][10][11][12][13]. In the mammalian brain, arousal has been largely associated with the activity of the locus coeruleus (LC) [17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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The eyes reflect an internal cognitive state hidden in the population activity of cortical neurons

Johnston

Snyder

Khanna

et al. 2020

Preprint

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SummaryDecades of research have shown that global brain states such as arousal can be indexed by measuring the properties of the eyes. Neural signals from individual neurons, populations of neurons, and field potentials measured throughout much of the brain have been associated with the size of the pupil, small fixational eye movements, and vigor in saccadic eye movements. However, precisely because the eyes have been associated with modulation of neural activity across the brain, and many different kinds of measurements of the eyes have been made across studies, it has been difficult to clearly isolate how internal states affect the behavior of the eyes, and vice versa. Recent work in our laboratory identified a latent dimension of neural activity in macaque visual cortex on the timescale of minutes to tens of minutes. This ‘slow drift’ was associated with perceptual performance on an orientation-change detection task, as well as neural activity in visual and prefrontal cortex (PFC), suggesting it might reflect a shift in a global brain state. This motivated us to ask if the neural signature of this internal state is correlated with the action of the eyes in different behavioral tasks. We recorded from visual cortex (V4) while monkeys performed a change detection task, and the prefrontal cortex, while they performed a memory-guided saccade task. On both tasks, slow drift was associated with a pattern that is indicative of changes in arousal level over time. When pupil size was large, and the subjects were in a heighted state of arousal, microsaccade rate and reaction time decreased while saccade velocity increased. These results show that the action of the eyes is associated with a dominant mode of neural activity that is pervasive and task-independent, and can be accessed in the population activity of neurons across the cortex.

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Section: Discussionmentioning

confidence: 99%

Section: Correlations Between the Eye Metrics Over Timementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The eyes reflect an internal cognitive state hidden in the population activity of cortical neurons

Johnston

Snyder

Khanna

et al. 2020

Preprint

View full text Add to dashboard Cite

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New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

David

Malhotra

2022

Ann Clin Transl Neurol

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There is clear, early noradrenergic dysfunction in Alzheimer's disease. This is likely secondary to pathological tau deposition in the locus coeruleus, the pontine nucleus that produces and releases noradrenaline, prior to involvement of cortical brain regions. Disruption of noradrenergic pathways affects cognition, especially attention, impacting memory and broader functioning. Additionally, it leads to autonomic and neuropsychiatric symptoms. Despite the strong evidence of noradrenergic involvement in Alzheimer's, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof‐of‐principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin‐sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone. Here, we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer's disease.

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Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

Ehrenberg

Kelberman

Liu

et al. 2023

Alzheimer's & Dementia

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The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here,

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Pupil Size as a Window on Neural Substrates of Cognition

Cited by 446 publications

References 186 publications

The eyes reflect an internal cognitive state hidden in the population activity of cortical neurons

The eyes reflect an internal cognitive state hidden in the population activity of cortical neurons

New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

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